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A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression
Accepted Manuscript A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression
Chutima Roomruangwong, George Anderson, Michael Berk, Drozdstoy Stoyanov, André F. Carvalho, Michael Maes PII: DOI: Reference:
S0278-5846(17)30625-5 doi: 10.1016/j.pnpbp.2017.09.015 PNP 9229
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
31 July 2017 12 September 2017 17 September 2017
Please cite this article as: Chutima Roomruangwong, George Anderson, Michael Berk, Drozdstoy Stoyanov, André F. Carvalho, Michael Maes , A neuro-immune, neurooxidative and neuro-nitrosative model of prenatal and postpartum depression. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/j.pnpbp.2017.09.015
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A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression
Chutima Roomruangwong a, George Anderson b, Michael Berk
, Drozdstoy Stoyanov e, André
a,c,e
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F. Carvalho f, Michael Maes
c,d
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
b
CRC, Scotland and London, UK
c
Impact Strategic Research Center, Deakin University, Geelong, Australia
d
Orygen, the National Centre of Excellence in Youth Mental Health and Orygen Research
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e
Medical University of Plovdiv, Department of Psychiatry and Medical Psychology, Technology
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Center for Emergency Medicine
Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of
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f
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a
words: depression, cytokines, inflammation, leaky gut, autoimmune, oxidative and
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Key
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Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
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nitrosative
Corresponding author:
Prof. Dr. Michael Maes, M.D., Ph.D. IMPACT Strategic Research Centre, School of Medicine Deakin University,
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PO Box 281 Geelong 3220 Australia [email protected]
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https://scholar.google.com.br/citations?user=1wzMZ7UAAAAJ&hl=pt-BR&oi=ao
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Abstract A large body of evidence indicates that major affective disorders are accompanied by activated
neuro-immune,
neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways.
Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a
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lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum
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depression. This review provides a critical appraisal of available evidence linking IO&NS
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pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including
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perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan
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catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including
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increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites,
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lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-
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inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the
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pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do
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not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression.
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Key
words: depression, cytokines, inflammation, leaky gut, autoimmune, oxidative and
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nitrosative
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1. Introduction 1.1. Introduction to mood disorders There is considerable evidence that major depression and bipolar disorder are both accompanied by activated neuro-immune pathways (Berk et al., 2011; Berk et al., 2013; Maes,
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1995). Several meta-analyses have shown higher levels of inflammatory biomarkers, including;
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interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and IL-1β, the soluble IL-2 receptor,
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the IL-1 receptor antagonist (IL-1ra), and C-reactive protein (CRP) in patients with major depressive disorder when compared with non-depressed controls (Dowlati et al., 2010; Howren
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et al., 2009; Köhler et al., 2017a; Köhler et al., 2017b; Liu et al., 2012). A recent meta-analysis
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also shows that serum zinc, a negative acute phase reactant and immune-inflammatory biomarker, is significantly decreased in major depressive disorder (Swardfager et al., 2013). nitro-oxidative
or
nitrosative
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Increased
damage
to
proteins,
lipids,
DNA
and
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mitochondria indicates that activated neuro-oxidative and neuro-nitrosative pathways play a key role in major depressive disorder and bipolar disorder (Berk et al., 2011; Maes et al., 2011a).
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Recently, two new pathways related to the activation of neuro-immune, neuro-oxidative and
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neuro-nitrosative stress (IO&NS) pathways were discovered in major depression. Firstly, depression is accompanied by disorders of the gut-brain axis (Maes et al., 2008a; Maes et al.,
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2012c; Slyepchenko et al., 2017) as exemplified by increased immunoglobulin (Ig)A/IgM responses to antigens and LPS from Gram-negative commensal gut bacteria, as a consequence of increased bacterial translocation and increased gut permeability (leaky gut) and gut-inflammation (Köhler et al., 2016; Maes et al., 2008a; Maes et al., 2012c). Secondly, major depression is also accompanied by increased IgM-mediated autoimmune responses to oxidatively damaged cell membrane lipids and nitrosylated proteins (Köhler et al., 2016).
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1.2. Introduction to prenatal and postpartum depression Recent data indicates a particular role of neuro-immune pathways in the pathophysiology of puerperal blues and postpartum depression (Anderson and Maes, 2013; Osborne and Monk,
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2013). Puerperal blues is an emotional response consisting of mood lability, crying spells,
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anxiety, irritability and insomnia occurring in the first few days following childbirth, and
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spontaneously resolving within 2 weeks. This condition is very common (40-85%) among puerperiae and therefore seen as a normal physiological response. Postpartum depression occurs
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in 10-25% of new mothers (Anderson and Maes, 2013; Brockington, 2004; Osborne and Monk,
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2013). Various risk factors for postpartum depression have been identified, including obstetric complications, such as preeclampsia, and psychosocial factors, such as stressors during
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pregnancy, low socioeconomic status, and a poor support system (Hirst and Moutier, 2010;
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Hoedjes et al., 2011). Postpartum depression is predicted by lifetime histories of major depression, postpartum depression, bipolar disorder, premenstrual syndrome (PMS) and prenatal
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depressive symptoms at the end of term (Clout and Brown, 2015; Eberhard-Gran et al., 2014;
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Lefkovics et al., 2014; Lydsdottir et al., 2014; Roomruangwong et al., 2017 ; Roomruangwong et al., 2016b) (Dudek et al., 2014; Jaeschke et al., 2016; Rybakowski et al., 2007).
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Figure 1 shows the association between prenatal and postpartum depression and how both disorders are associated with mood disorders (MOOD) and PMS. Prenatal depression is additionally associated with pregnancy-specific changes (including changes in hormone and IO&NS pathways that develop during pregnancy), whilst postpartum depression is predicted by prenatal depressive symptoms and a lifetime history of postpartum depression as well as pregnancy- or delivery-related stressors, including cesarean section and obstetric complications.
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Insert Figure 1 here.
Most previous research has focused on the biological and clinical predictors of
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postpartum depression usually measuring the severity of postpartum depression with the
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Edinburgh Postnatal Depression Scale (EPDS) (Eberhard-Gran et al., 2014; O'Connor et al.,
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2016). Nevertheless, some pregnancy-specific changes, including lower zinc and increased Creactive protein (CRP), are strongly related to prenatal depression and may predict postpartum
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depression (Roomruangwong et al., 2017c), suggesting that the pathophysiology of postpartum
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depression may partly overlap with and be determined by that of prenatal depression (Roomruangwong et al., 2017c). In addition, pregnancy-specific changes, including alterations in status,
activation
of
the
hypothalamic-pituitary-adrenal
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hormonal
(HPA)-axis,
immune
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activation, oxidative stress and antioxidant status (see below) alter the homeostatic balance between pro-inflammatory and oxidative pathways with immune regulatory and antioxidant
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pathways. Consequently, minor shifts in this new homeostatic set point during pregnancy could
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be additional risk factors for prenatal and thus postpartum depression. However, no previous papers have addressed the impact of these different factors on the neuro-immune, neuro-
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oxidative and neuro-nitrosative (IO&NS) pathways in pregnancy and the pathophysiology of prenatal and postpartum depression. Importantly, it can be very difficult to separate the symptoms and consequences of depression from those of physiosomatic (formerly psychosomatic) symptoms, including chronic fatigue, autonomic symptoms, hyperalgesia, somatic presentations and neurocognitive disorders (Anderson et al., 2012). Recently, we reported that the physiosomatic symptoms that emerge
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during pregnancy including chronic fatigue, back pain, muscle cramps, pain, dyspepsia and gastro-intestinal symptoms, are associated with IO&NS pathways. The current article provides a critical review of available evidence on the role of IO&NS pathways in prenatal and postpartum depression. Table 1 lists the pathways discussed (and their
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most important biomarkers) during pregnancy as well as prenatal and postpartum depression.
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This table also shows their association with affective and physiosomatic symptoms. The
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pathways are: 1) neuro-immune pathways (including cytokines, immune and inflammatory biomarkers); 2) the TRYCAT pathway (including serum concentrations of tryptophan and
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TRYCATs as well as IgA/IgM responses to TRYCATs); 3) neuro-oxidative pathways (including
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lipid peroxidation, protein oxidation, lowered levels of antioxidants); 4) neuro-nitrosative pathways (including nitric-oxide production and nitrosylation of proteins); 5) gut-brain pathway
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(including IgA/IgM responses to gut bacteria); and 6) natural autoimmune pathways (including
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IgM responses to malodialdehyde (MDA) and nitrosylated proteins).
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2. Methods
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A narrative review was conducted, following a literature searching PubMed, Google scholar, Medline, and Scopus database by combining the keywords “prenatal-depression”, inflammation”,
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“immune,
“oxidative”,
“ROS”,
“RNS”,
“nitric
oxide”,
“nitrosative”,
“tryptophan”, “tryptophan catabolites”, “kynurenine”, “IDO”, “leaky gut”, “gut-brain”, and “microbiome”. We restricted the literature search to clinical studies in the English-language published between 1990 until 2017.
3. Results
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3.1. Introduction to non-pregnancy-related major affective disorders Depression is a common disorder, characterized by depressed mood, loss of interest and pleasure, disturbances in energy, sleep and appetite, physiosomatic symptoms, and cognitive deficits. In major depressive disorder, increased levels of immune-inflammatory biomarkers (e.g.
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IL-1, IL-6, TNF-α, and CRP are evident in the plasma and cerebrospinal fluid (CSF), influencing
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the progression and severity of clinical depression in different populations (Maes et al., 2011d;
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Noto et al., 2014). Immune activation may impact the pathophysiology of a meaningful subset of depression presentations as indicated by different neuro-immune pathways, which along with
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O&NS contribute to a deteriorating course of recurrent presentations, a process referred to as
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neuroprogression (Leonard and Maes, 2012; Moylan et al., 2013; Slyepchenko et al., 2016). Alterations in the serotonergic system, including a decrease in the serotonin precursor
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tryptophan have classically been linked to depression (Meltzer and Maes, 1995). Raised levels of
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pro-inflammatory cytokines drive the induction of indoleamine-2, 3-dioxogyynase (IDO), an enzyme that catalyzes the first and rate-limiting step in the TRYCAT pathway, thereby depleting
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plasma tryptophan as a precursor of serotonin (Munn and Mellor, 2013). Different TRYCATs
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have different biological effects ranging from neurotoxicity to neuroprotection, pro- to antiinflammatory, and excitatory to inhibitory including in neurons and glia (Leonard and Maes,
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2012; Maes et al., 1994b). The TRYCAT pathway can also be stimulated by cortisol, which induces tryptophan 2, 3-dioxygenase (TDO), with TDO activation contributing to tryptophan depletion. There is some evidence that the TRYCAT pathway is activated in major depression (Maes et al., 2011b; Maes et al., 2002). Major depressive disorder is also commonly accompanied by lower antioxidant levels, including total radical trapping antioxidant potential (TRAP) (Vargas et al., 2013), paraoxonase
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1 (PON1) (Moreira et al., 2017), zinc, high-density lipoprotein cholesterol and vitamin E as well as lower ω3 polyunsaturated fatty acids (ω3 PUFAs) (Maes et al., 1994a; Maes et al., 1996). These factors regulate cellular resilience to diverse oxidative insults with lowered levels increasing the susceptibility to lipid peroxidation, including from raised levels of MDA
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(Jiménez-Fernández et al., 2015; Liu et al., 2015), and protein oxidation, as indicated by an
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increase in advanced oxidation protein products (AOPP) (Gomes et al., 2017). Recently,
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increased natural IgM-mediated autoimmune responses to oxidatively modified neoepitopes or
MDA (Maes et al., 2011c; Maes et al., 2007).
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oxidative specific epitopes (OSEs) have been observed in major depressive disorder, including to
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Major depression is also accompanied by increased NO production and iNOS activity (Gałecki et al., 2012; Maes et al., 2011a). Persistent increases in NO levels when coupled with
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raised levels of superoxide (O 2−) can lead to the formation of peroxynitrite and cell damage
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(Maes, 2008; Maes et al., 2011a). In physiological conditions, reactive nitrogen species (RNS), including NO and peroxynitrite (ONOO−), are tightly regulated by intrinsic antioxidant
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mechanisms with suppressed levels of antioxidants contributing to excessive RNS and
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consequent damage to cellular membranes and/or mitochondria (Maes et al., 2011a). Persistently elevated NO levels can lead to protein nitrosylation and thereby to the formation of new NO-
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adducts (NO-neoepitopes) (Maes, 2008; Maes et al., 2012b; Maes et al., 2011a). Importantly, some of these newly formed NO-adducts can trigger autoimmune responses directed against “nitrosative specific epitopes” (NSEs), resulting in deleterious neurotoxic effects (Boullerne et al., 2002; Maes et al., 2012b; Maes et al., 2011a). Major depression without pregnancy particularly chronic depression is also accompanied by increased IgA/IgM responses to antigens and LPS from gram-negative gut bacteria, which
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accompanies increased gut permeability and gut-driven inflammation (Maes et al., 2008a; Maes et al., 2012c; Maes et al., 2011d). Increased bacterial translocation is accompanied by inflammatory responses and increased autoimmune responses to self-antigens, including lowdensity lipoprotein cholesterol and MDA, indicating that a leaky gut may induce inflammation,
3.2.1. Pregnancy-specific changes in immune pathways
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3.2. Pregnancy-specific changes in IO&NS pathways
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oxidative stress and autoimmune responses to OSEs (Maes et al., 2013).
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Pregnancy is associated with changes in immune responses thereby allowing the
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development of the fetal allograft (Galindo-Sevilla et al., 2014; Leff-Gelman et al., 2016). Pregnancy comprises three relevant immunological adaptation phases. During early pregnancy,
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an immune-inflammatory response is triggered when the blastocyst breaks through the epithelial
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lining of the uterus for implantation, followed by the trophoblast replacement of the endothelium, and vascular smooth muscle of the maternal blood vessels to provide fetal blood
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supply (Abrahams et al., 2004; Dekel et al., 2010; Mor et al., 2011). Moreover, trophoblast cells
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induce monocytes and T helper (Th)-1 cells to secrete cytokines, including IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and growth-regulated protein alpha (GRO-α) (Mor et al.,
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2011), which can then recruit immune cells to the implantation site (Abrahams et al., 2004; Mor et al., 2005). The latter process may modulate the differentiation of immune cells (Fest et al., 2007). High levels of IL-6, IL-8, and TNF-α are also secreted by endometrial cells as well as by cells of the immune system (Manaster and Mandelboim, 2010). When pregnancy progresses to the second stage, where the mother, placenta, and fetus are symbiotic, the immune system acquires a more anti-inflammatory state (Mor et al., 2011). Finally, during late pregnancy, when
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the fetus is prompt to be delivered, immune cells influx into the myometrium in order to promote an inflammatory response (Romero et al., 2006), promoting uterine contractions, birth of the baby, placental rejection and defense against puerperal sepsis (Mor et al., 2011). End of term pregnancy is accompanied by increased serum levels of IL-6, IL-1RA,
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leukemia inhibitory factor receptor (LIF-R) and increased CRP but lowered zinc levels (Maes et
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al., 2000; Roomruangwong et al., 2017c). These findings in aggregate indicate that end of term
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pregnancy is accompanied by immune activation, an inflammatory response (increased IL-6 and CRP and lowered zinc), and increased negative immunoregulatory responses (increased sIL-1RA
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and LIF-R levels). Hence, at the end of term, pregnancy is characterized by indications of
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increased peripheral inflammation, which is kept in balance by increases in immune regulatory processes. This is achieved partly via immune mechanisms as well as increased hormonal
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activities, including increased HPA-axis activity and progesterone levels (Maes et al., 2001).
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After delivery, however, there may be a breakdown in these immune dampening mechanisms as exemplified by significantly increased serum levels of IL-6, sIL-6R and sIL-1RA
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concentrations and lowered LIF-R levels in the early puerperium (Maes et al., 2001). This
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indicates that the early puerperium is characterized by increased IL-6 trans-signaling (Maes et al., 2014a) and IL-1 signaling (Maes et al., 2012e), whereas the anti-inflammatory effects of LIF-
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R (Hunt et al., 2013) levels are sharply reduced. All in all, while pregnancy is characterized by a new balance between inflammatory and anti-inflammatory mechanisms, the early puerperium appears to be accompanied by a more pro-inflammatory state.
3.2.2. Pregnancy-specific changes in TRYCAT pathway activity
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Maternal total tryptophan is elevated in early pregnancy and returns to slightly below normal during mid-gestation, and decreases again by 25% during late pregnancy (Schröcksnadel et al., 1996). TDO activity is lowered during early to mid-pregnancy, but enhanced in late pregnancy. TDO is induced by glucocorticoids whilst inhibited by estrogen and progesterone
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(Badawy, 1988). TDO mRNA expression in the decidualized endometrium is increased around
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the implanted embryo, suggesting its involvement in the implantation process through the
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regulation of tryptophan levels at the implantation site (Tatsumi et al., 2000). IDO is highly present in significant amounts in the placenta (Kudo et al., 2004; Ligam et al., 2005;
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Manuelpillai et al., 2005; Yamazaki et al., 1985). Placental IDO, kynureninase and 3-
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hydroxyanthranilic acid oxidase activity may be enhanced by cytokines (e.g. IFN-γ), which may be released in response to infection and inflammation. Placental IDO is suppressed by
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progesterone, especially during decidualization (Kudo et al., 2004). There is evidence suggesting
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that during early to mid-pregnancy, tryptophan degradation occurs mainly via TDO, whereas IDO may become more important during mid- to late pregnancy (Badawy, 2015; Kudo et al.,
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2004; Ligam et al., 2005).
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Maternal plasma tryptophan is significantly decreased at the end of term and further reduced in the days after delivery. This indicates IDO induction at the end of term with further
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stimulation after delivery through immune activation (Maes et al., 2001). Moreover, in pregnant women at the end of term, the kynurenine/tryptophan (K/T) quotient (indicating IDO activity) is significantly increased, while the K/T quotient further increases in the early puerperium in association with immune activation and enhanced inflammatory responses (Maes et al., 2002). This shows that IDO activity is enhanced at the end of pregnancy and further increases in early puerperium and that this phenomenon is partly immune- mediated.
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3.2.3. Pregnancy-specific changes in O&NS pathways In normal pregnancy, there is an increase in nitro-oxidative processes (Ardalić et al., 2014; Ferguson et al., 2015; Mihu et al., 2012), characterized by a transient increase in the
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production of reactive oxygen species (ROS), which is partially counterbalanced by an increase
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in antioxidant mechanisms (Burton and Hung, 2003; Mihu et al., 2012). A certain amount of
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oxidative stress based redox signaling during pregnancy is necessary for embryonic and fetal growth (Dennery, 2010). A new balance between ROS and antioxidants is necessary for
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decidualization, normal fetal organogenesis and development during pregnancy (Al-Gubory et
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al., 2010; Dennery, 2004). At the end of term, significantly increased levels of AOPP and nitric oxide metabolites (NOx) coupled to a decrease in total radical trapping potential (TRAP), zinc, -
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sulfhydryl (-SH) groups and peroxides (LOOH) levels are evident (Roomruangwong et al., in
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press). These findings suggest that pregnancy is accompanied by very high levels of protein oxidation (at the expense of peroxide production) and NOx production coupled with lowered
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antioxidant activity. Moreover, during pregnancy, there are marked changes in lipid metabolism,
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characterized by significant increases in total cholesterol levels in association with increased oxidative stress (Toescu et al., 2002).
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Increased O&NS in pregnancy leads to more negative outcomes for mother and baby, e.g. due to the impairment of endothelial and vascular functions, and increased apoptotic activity in the placenta (Saad et al., 2016). Increased O&NS also raises the likelihood of the atherosclerosis and endothelial dysfunction that are observed in pre-eclampsia (Roberts and Hubel, 1999). A disturbed placental milieu with high O&NS may induce fetal programming of adult disease via increased DNA damage and mutations (Saad et al., 2016). Due to their low antioxidant content,
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fetal pancreatic β-cells are extremely vulnerable to damage by ROS (Simmons, 2006), which may lead to permanent pancreatic cell functional alterations and the onset of later diabetes (Kamel et al., 2014). Increased AOPP levels at the end of term are associated with lowered cord length and an increased risk for caesarian section, whereas lowered PON1 activity at the end of
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term is associated with increased labor duration and neonatal problems, including more night
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time awakenings and sucking problems in the early neonatal period (Roomruangwong et al., in
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press). Moreover, increased protein nitrosylation is strongly associated with specific pregnancy complications such as pre-eclampsia and gestational diabetes, whist nitrosylation may also
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disrupt normal placental functions (Lyall et al., 1998; Myatt, 2010). Overall, pregnancy is
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characterized by increased protein oxidation and NO production coupled to lowered levels of key
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antioxidants, including zinc.
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3.2.4. Pregnancy-specific changes in bacterial translocation Adaptation of the gastrointestinal tract, e.g. increased size of villus, increased intestinal
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motility and transit time, is important during pregnancy to ensure the maintenance of high
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metabolic demands of the developing fetus (Astbury et al., 2015). Moreover, there are changes in the gut microbiome during pregnancy (Koren et al., 2012), including decreased microbial alpha
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diversity (types of sequences in each sample) and an increase in beta diversity (distribution of different types among samples) (Turnbaugh et al., 2006), with increased amounts of bacteria species capable of sugar fermentation (e.g. Firmicutes species) (Koren et al., 2012). There is also an increased population of Lactobacillus, Streptococcus, Enterococcus, and Proteobacteria during the third trimester of pregnancy (Koren et al., 2012; Mukhopadhya et al., 2012; Turnbaugh et al., 2006). Moreover, estrogen may increase gut permeability and proliferation of
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gram-negative bacteria in the gut which if undefended can lead to portal endotoxemia (Farhat et al., 1996). Studies demonstrate an association of LPS exposure and increased maternal serum corticosterone, IL-1β levels, injury to placental tissue and increased rate of pregnancy loss (Kirsten et al., 2013; Pontillo et al., 2013).
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Pregnancy is accompanied by lowered translocation of Gram-negative bacteria and thus
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lowered gut permeability as indicated by significantly decreased levels of IgA responses to
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Gram-negative bacteria, suggesting that pregnant women could be protected against the development of a ‘leaky’ gut (Roomruangwong et al., 2017a). In this respect, in vitro and
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preclinical studies show that estrogen may induce a 2-8 fold increase in intestinal mucus
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viscosity resulting in decreased gut permeability (Braniste et al., 2009; Diebel et al., 2015; Doucet et al., 2010; Looijer-van Langen et al., 2011). Treatment with progesterone may increase
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mucus level production in the duodenum and attenuate mucosal injury and microvascular
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leakage (Drago et al., 1999). Therefore, it may be suggested that pregnant women may be protected against leaky gut by increased progesterone and maybe increased estrogen levels
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(Roomruangwong et al., 2017a).
3.2.5. Pregnancy-specific changes in autoimmune responses autoimmune
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Many
diseases
characteristically
flare
up
during
early
pregnancy
(implantation) and perinatal periods, and may recur upon subsequent pregnancies (Amino et al., 1999; Gleicher, 2007; Ruiz-Irastorza et al., 1996; Schramm et al., 2006; Sliwa et al., 2006), including thyroid disease, autoimmune hepatitis and systemic lupus erythematosus. Subclinical autoimmunity has been shown to be associated with recurrent pregnancy loss (Dudley and Branch, 1991; Gleicher et al., 1993; Perricone et al., 2012). Pregnancy is also associated with a
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shift toward a T helper (Th)-2 type immune response (Mor et al., 2011) and increased IgM levels in pregnant animal models (Muzzio et al., 2014), while studies on autoantibody levels in pregnant women have yielded conflicting results (D’Armiento et al., 1980; Farnam et al., 1984; Levy, 1982; Mavridis et al., 1992) with variability depending on the type of autoimmune
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responses assessed.
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At the end of term attenuated natural IgM-mediated responses to OSEs, including MDA,
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have been found indicating a suppression of this part of the compensatory anti- inflammatory reflex system (CIRS), which is an adaptive anti-inflammatory response of the immune system
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that attenuates an excessive inflammatory response caused by pathogens or immune trauma
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(Maes et al., 2012a; Roomruangwong et al., 2017b). Moreover, at the end of term, IgM responses to OSEs were significantly correlated with IgM and IgA responses to Gram-negative commensal
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bacteria, including Citrobacter koseri, Klebsiella pneumoniae and Morganella morganii
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(Roomruangwong et al., 2017a). This could indicate that the lowered IgM responses to OSEs at the end of pregnancy are in part attributable to lowered bacterial translocation.
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Most importantly, at the end of term, we found an inverse relationships between IgM
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responses to MDA, on the one hand, and O&NS biomarkers (AOPP and NOx and diverse indices of increased nitro-oxidative potential), on the other (Roomruangwong et al., submitted).
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These results provide initial evidence that natural autoimmune responses to MDA exert protective effects attenuating O&NS pathways via immune dampening and anti-oxidant effects. Moreover, the lowered natural autoimmune responses at the end of pregnancy could reflect attenuated regulatory responses thereby contributing to increased IO&NS pathways and maybe increased autoimmune potential during pregnancy (Frostegård, 2013; Rahman et al., 2016;
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Roomruangwong et al., 2017b). Table 1 (right column) summarizes the pregnancy-specific changes in the 6 different IO&NS pathways.
4. IO&NS Pathways in prenatal depression
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4.1. Neuro-immune pathways in prenatal depression
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In the early puerperium increased levels of IL-6 and IL-6R concentrations are associated
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with increased self-reported levels of depression, while increased serum IL-6 and IL-1RA coupled with lowered LIF-R levels, are associated with self-reported anxiety (Maes et al., 2000).
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These findings suggest that increased IL-6 trans-signaling is associated with depressive
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symptoms in the early puerperium and increased inflammatory and IL-1 signaling may be associated with anxiety symptoms. However, the common self-reported anxiety and depression
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in the days after delivery mostly indicate puerperial blues rather than postpartum depression.
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Moreover, we were unable to detect any significant associations between these inflammatory changes in the early puerperium and postpartum depression within the first few months after
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delivery. Interestingly, in the early puerperium sIL-1RA levels are significantly higher in
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primiparae as compared with multiparae (Maes et al., 2004), suggesting that parity may modulate IL-1 signaling following delivery.
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Other studies during the prenatal period yielded mixed results (Azar and Mercer, 2013; Blackmore et al., 2011; Cassidy-Bushrow et al., 2012; Christian et al., 2009; D’Anna et al., 2011; Maes et al., 2000). Previous work suggested that some inflammation-related pregnancy morbidities, including pre-eclampsia, preterm birth and gestational diabetes, are associated with prenatal depression (Alder et al., 2007; Kharaghani et al., 2012; Kozhimannil et al., 2009; Kurki et al., 2000; Orr et al., 2002). Moreover, studies in specific populations (e.g. African American,
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and those with high body mass index (BMI)) found an increased rate of prenatal depression in association with increased levels of IL-6 (Blackmore et al., 2014) and adverse obstetric outcomes, including pre-eclampsia, low birth weight and premature ruptured of the membranes (PROM) (Gomez et al., 1995; Saito, 2000; Santhanam et al., 1991). Karlsson et al. observed that
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IL-12, IL-9 and IL-13, and higher IFN/IL-4 ratio and IL-5 correlated positively with depressive
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symptoms, whereas IL-6 and TNF-α were not related to prenatal symptoms (Karlsson et al.,
CR
2017). Leff-Gelman et al. proposed that the same immune-inflammatory processes involved in
US
major depression operate in the placenta during perinatal depression. Thus, activation of TollLike Receptor (TLR)2 and TLR4 in placental immune cells could promote a shift towards a
AN
Th1/Th17 bias with increased production of pro-inflammatory cytokines triggering depressive symptoms (Leff-Gelman et al., 2016). Higher CRP levels at the end of term are strongly
M
associated with severity of prenatal depressive symptoms, indicating that when pregnancy-
ED
related inflammation increases, depressive symptoms may emerge at the end of term
PT
(Roomruangwong et al., 2017c).
However, recent studies also found inverse associations between prenatal depressive
CE
scores and levels of inflammatory markers. In a pilot study, Shelton et al. observed that prenatal
AC
depressive symptoms were inversely associated with IL-1, TNF-α and IL-17 (Shelton et al., 2015). Edvinsson et al. (Edvinsson et al., 2017) reported that inflammatory markers were downregulated in prenatal depression, for example macrophage colony-stimulating factor, TNFrelated apoptosis inducing ligand and fractalkine. All in all, these results suggest that proinflammatory cytokines may be less involved in the pathophysiology of prenatal depression as compared to non-pregnant mood disorders.
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The HPA-axis may be a potential mediator between prenatal depression and the inflammatory response (Horowitz et al., 2013; Sun et al., 2011). During pregnancy, cortisol output is increased while the HPA-axis is less reactive to glucocorticoid feedback (Maes et al., 1992). The majority of maternal cortisol is converted to an inactive form (cortisone) by the
T
enzyme 11-beta hydroxysteroid dehydrogenase (11 β -HSD) (Murphy et al., 1974), and there is
IP
evidence that the 11β-HSD1 enzyme activity may be higher in M2 than in M1 macrophages
CR
(Chinetti-Gbaguidi et al., 2012). There is a negative correlation between those inflammatory markers and cortisone levels in healthy pregnant women but not in women with prenatal
US
depression (Hellgren et al., 2013; Horowitz et al., 2013). These findings suggest that prenatal
AN
depression may be associated with an incomplete switch from a predominant M2 to M1 phenotype with connections between HPA-axis dysregulation, inflammation, and prenatal
M
depression (Brown et al., 2014). In this respect, Gelman et al proposed that dysfunctions of the
PT
the fetus (Gelman et al., 2015).
ED
HPA-axis may be caused by immune and placental factors leading to cortisol-induced toxicity to
CE
4.2. The TRYCAT pathway in prenatal depression In the early puerperium, an inverse association was detected between lowered L-
AC
tryptophan levels and self-reported depressive and anxiety symptoms, indicating that lowered availability of L-tryptophan to the brain is associated with puerperal blues (Maes et al., 1992). Nevertheless, a follow-up study showed that the lowered availability of plasma tryptophan to the brain in the early puerperium, which is in part mediated by inflammatory processes, is not related to either indicants of post-partum blues or postpartum depression arising some months later (Maes et al., 2001). More importantly, the increases in plasma kynurenine and the K/T quotient
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from the end of term and early puerperium (which are both related to immune activation) were significantly associated with indices of puerperal depressive and anxiety blues but not with later postpartum depression (Maes et al., 2002). All in all, these results provide evidence that an increased catabolism of tryptophan into kynurenine arising from immune activation in the early
T
puerperium, may be related to puerperal blues, but not postpartum depression. Bailara et al.
IP
(Baïlara et al., 2006) reported that a lowered availability of L-tryptophan to the brain as a
CR
consequence of changes in competing amino acids partly accounts for puerperal blues. Veen et al. reported that increased L-tryptophan breakdown and increased kynurenine levels in the
US
postpartum period do not occur in women with postpartum depression and that kynurenine is
AN
significantly lower in patients with postpartum depression (Veen et al., 2016). Using a new assay to measure TRYCAT pathway activity (namely IgA and IgM
M
responses to TRYCATs) we could not verify that TRYCAT pathway activity at the end of term
ED
is associated with prenatal depression or postpartum depressive symptoms. TRYCAT pathway activation was significantly associated with a lifetime history of PMS rather than with prenatal
PT
depression or a lifetime history of depression. Nevertheless, lowered IgA responses to anthranilic
CE
acid were significantly associated with prenatal depression (Roomruangwong et al., 2017 ). In addition, we found that the TRYCAT pathway is tightly regulated by many different inputs, inflammatory
AC
including
signals,
nitrosative
stress,
bacterial translocation,
and
regulatory
autoimmune responses (Roomruangwong et al., 2017a; Roomruangwong et al., 2017b).
4.3. Oxidative stress and nitrosative stress in prenatal depression Recent studies showed that oxidative parameters, namely MDA, superoxide dismutase, catalase, total antioxidant status, total oxidant status, and oxidative stress index levels in the fetal
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cord blood of depressed mothers were not significantly different from healthy pregnant controls, suggesting that the placental barrier may protect against oxidative stress (Camkurt et al., 2017; Camkurt et al., 2016b). However, another study performed on fetal cord blood reported decreased levels of glutathione peroxidase among prenatally depressed versus control mothers
glutathione peroxidase levels in the fetal circulation may reflect inadequate
IP
Decreased
T
without significant changes in the antioxidant enzyme myeloperoxidase (Camkurt et al., 2016a).
CR
compensation for oxidative activity in prenatal depression, resulting in an oxidative intrauterine environment, leading to disturbances in fetal brain development and plasticity (Camkurt et al.,
US
2016a). Prenatal depression has also been demonstrated to be a risk factor for cardiovascular
AN
diseases during pregnancy putatively via activation of oxidative stress and immune-inflammatory pathways (Kurki et al., 2000; Nicholson et al., 2016).
M
Recently, a significant association was found between increased O&NS, lowered
ED
antioxidant (namely: –SH groups, zinc, TRAP) and LOOH levels and prenatal depressive symptoms (Roomruangwong et al., in press). The most important indicators of O&NS associated
PT
with prenatal depression were increased AOPP and NOx, indicating protein oxidation and
CE
increased NO production leading to nitrosative and nitro-oxidative stress. The inverse association between lowered levels of –SH groups and prenatal depressive symptoms may be explained by
AC
increased use of –SH groups for nitrosothiol (SNO) synthesis, while the inverse association between peroxides and depressive symptoms may be explained by increased use of peroxides during AOPP synthesis and inhibition of peroxides by AOPP (Bordignon et al., 2014; Piwowar, 2010). This suggests that prenatal depression is associated with protein oxidation rather than lipid peroxidation (Roomruangwong et al., in press). The inverse association between TRAP and prenatal depression may indicate that lowered antioxidant defenses are associated with the onset
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of depressive symptoms at the end of term. Moreover, end of term serum zinc was strongly and inversely associated with prenatal depressive symptoms. Thus, increased protein oxidation and NOx production, lowered production of peroxides and lowered antioxidant defenses occur in normal pregnancy, but when protein oxidation and/or NOx production further increase or when
T
antioxidant levels further decrease depressive symptoms may emerge. All in all, these findings
IP
indicate that pregnancy-associated activation of protein oxidation and NO pathways are
CR
associated with the onset of depressive symptoms at the end of term (Roomruangwong et al.,
US
2017d).
AN
4.4. Bacterial translocation in prenatal depression
As discussed in section 3.2.3., pregnant women show significantly lowered IgA
M
responses to Gram-negative bacteria, indicating lowered bacterial translocation. In addition, in
ED
pregnant women, there is a lack of significant associations between IgA/IgM responses to Gramnegative bacteria and prenatal depression (Roomruangwong et al., 2017a). These negative
PT
findings contradict the findings in major depression indicating increased gut permeability (Berk
CE
et al., 2013; Bested et al., 2013; Logan, 2015; Logan et al., 2016; Maes et al., 2008a; MartinSubero et al., 2016; Naseribafrouei et al., 2014; Slyepchenko et al., 2016). Nevertheless, in the
AC
same study, we found that higher IgA/IgM responses to Gram-negative bacteria are associated with increased levels of haptoglobin and TRYCATs, especially quinolinic acid and the quinolinic acid / kynurenic acid ratio (indicating neurotoxic potential), suggesting that increased bacterial translocation may induce immune-inflammatory responses and TRYCAT pathway activation thereby increasing neurotoxic potential. It should be stressed however that these phenomena are not related to prenatal depression. In conclusion, our findings suggest that
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pregnancy may protect against bacterial translocation, and that end of term mucosa-derived immune responses to Gram-negative bacteria may contribute to immune activation.
4.5. Natural autoimmune IgM responses to MDA / NO-adducts in prenatal depression
T
Pregnant women show increased thyroperoxidase antibodies, which are significantly
IP
associated with prenatal depression at 12 weeks gestation and at 4 and 12 weeks postpartum
CR
(Kuijpens et al., 2001). Another study, however, did not find a significant association between prenatal depression and increased IgM levels, although there were higher levels of IgG among
US
pregnant women with major depression than those with minor depression (Kianbakht et al.,
AN
2013). All in all, there is no clear evidence that common autoimmune responses may underpin perinatal depressive episodes.
M
At the end of term, the IgM responses directed against MDA were inversely associated
ED
with prenatal depressive symptoms (Roomruangwong et al., submitted). IgM response to MDA are natural regulatory autoimmune responses which help to clear debris, for example oxidatively
PT
damaged and dying or apoptotic cells expressing MDA (Maes et al., 2011a; Maes et al., 2011c;
CE
Tsuboi et al., 2013; Zheng et al., 2013). As such, these natural IgM antibodies target OSEs, thereby attenuating immune-inflammatory responses. Therefore, lowered IgM responses to
AC
MDA at the end of term are probably accompanied by lowered feedback on AOPP and NOx production and thus increased protein oxidation and nitrosylation leading to more antenatal depressive symptoms. Interestingly, IgM responses to NO-adducts were significantly and positively related to increased NOx levels indicating that measurements of IgM responses to NO-adducts reflect increased NO production and nitrosylation. In addition, IgM responses to NO-adducts were not
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only positively associated with a life time history of mood disorders, but also inversely with prenatal depressive symptoms (Roomruangwong et al., 2017b). This indicates that increased nitrosylation may be a trait marker of depression and bipolar disorder, and that increased autoimmune responses to NO adducts may be protective against prenatal depressive symptoms.
T
The IgM responses to NO-cysteinyl were significantly higher in women with a lifetime history of
IP
depression and therefore may possibly act as a trait marker of depression (Roomruangwong et
CR
al., 2017b). Thus, the pathophysiology of prenatal depression differs significantly from that of major depression with respect to increased nitrosylation and ensuing autoimmune responses to
US
NO-adducts. Overall, natural IgM responses to MDA and NO-adducts may be protective by
AN
attenuating nitro-oxidative pathways or depressive symptoms.
M
4.6. Do the biomarkers at the end of term predict postnatal depression?
ED
Since prenatal depression is the single best predictor of postpartum depression and since the latter is also predicted by lifetime histories of mood disorders, PMS and postpartum
PT
depression, it may be posited that the pathophysiology of postpartum depression is to a large
CE
extent related to that of prenatal depression, mood disorders and PMS (Roomruangwong et al., 2017 ; Roomruangwong et al., 2016b). In addition, the postnatal period is a period of bodily
AC
system stabilization back to the pre-pregnant state. This is a period where an accelerated immune-inflammatory response during labor continues into the early puerperium, while being mediated through both pro- and anti-inflammatory mediators for healing and involution (NilsenHamilton et al., 2003; Sennstrom et al., 2000). Finally, psychological stressors and exogenous stressors related to pregnancy and delivery (e.g. caesarian section, unwanted pregnancy, marital stress) may further enhance the activated IO&NS pathways in the early postnatal period.
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There is some evidence that immune changes at the end of pregnancy may predict postpartum depression. Thus, lowered levels of Clara cell protein (CC16), an endogenous antiinflammatory compound, are associated with postpartum depression some weeks later (Maes et al., 2000; Maes et al., 1999). Lowered levels of ω3 polyunsaturated fatty acids (PUFAs) at the
T
end of term predict postpartum depression some weeks later (De Vriese et al., 2003). ω3 PUFAs
IP
have anti-inflammatory effects by attenuating the activities of pro-inflammatory cytokines and
CR
therefore lowered ω3 PUFAs at the end of term may contribute to an overall increase in peripheral inflammation (De Vriese et al., 2003). Other end of term predictors of postpartum
US
depression include increased CRP, hematocrit, AOPP and NOx as well as lower zinc levels
AN
(Roomruangwong et al., 2017b; Roomruangwong et al., 2016a; Roomruangwong et al., 2017c). Interestingly, some of these biomarkers are also markers of prenatal depression (namely CRP,
M
zinc, AOPP, NOx), whereas other are not associated with prenatal depression (increased
ED
hematocrit). It is hypothesized that disorders in the crosstalk between the immune system and the HPA-axis may be associated with the onset of postpartum depression (Corwin and Pajer, 2008).
PT
There are now more reports on immune-inflammatory biomarkers during pregnancy
CE
predicting postpartum depression. IL-6 is one of the most frequent investigated inflammatory biomarkers showing a significant association with postpartum depression in some (Osborne and
AC
Monk, 2013), but not all studies (Maes et al., 2011d; Skalkidou et al., 2009). In another study, lowered levels of TNF- were associated with later postpartum depression (Corwin et al., 2015). Prenatal neopterin levels and pre- and post-natal T regulatory cells are increased in women who later developed postpartum depression (Krause et al., 2014). Accortt et al. (2015) were unable to detect associations between IL-6 and IL-10 and their ratio and depression scores (Accortt et al., 2016). IL-6 and IFN- were associated with postpartum depression in one study (Tsao et al.,
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2006), but not in another (Bränn et al., 2017). Nevertheless, the latter study reported that lowered levels of immune biomarkers (both pro- and anti-inflammatory) in late pregnancy predict postpartum depression, including signal transducing adaptor molecule- binding protein (STAMBP), AXIN-1, adenosine deaminase (ADA), sulfotransferase 1A1 (ST1A1), and IL-10 (Bränn et
T
al., 2017). STAM-BP is a zinc-metalloprotease, which is involved in cytokine-mediated
IP
intracellular signal transduction and cell growth (Suzuki et al., 2011). ADA is a dipeptidyl
CR
peptidase-4 (DPP IV) binding protein, which regulates T cell activation (Gines et al., 2002). Interestingly, DPP IV is significantly decreased in patients with non-pregnant major depression
US
(Maes et al., 1991). AXIN1 mediates cell growth, apoptosis and development and functions as a
AN
scaffold protein in TGF- signaling (Liu et al., 2006; Ye et al., 2015), while IL-10 functions as a regulatory cytokine with negative immunoregulatory properties with lower levels having some
M
association with suboptimal pregnancy outcomes (Sadowsky et al., 2003). ST1A1 functions as a
ED
catalyzer of sulfur conjugation for many neurotransmitters (Gamage et al., 2005). All in all, there
PT
is some evidence that prenatal depression-related changes in IO&NS pathways or IO&NS
CE
changes at the end of pregnancy may predict postpartum depression.
4.7. Physiosomatic symptoms at the end of term of pregnancy
AC
Physiosomatic symptoms such as fatigue, autonomic nervous system hyperactivity symptoms, hyperalgesia, gastro-intestinal symptoms and somatic presentations are common presentations in both psychiatric and medical disorders, including chronic fatigue syndrome (CFS) and multiple sclerosis (Morris and Maes, 2013). There is evidence of significant associations among physiosomatic symptoms in depression, CFS and somatization, and immuneinflammatory processes, including alterations in the tryptophan catabolite (TRYCAT) pathway
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(Anderson et al., 2012). Increased pro-inflammatory cytokine levels in depression are associated with the presence of fatigue and physiosomatic symptoms (Maes et al., 2012f). Serum IgM antibodies to OSEs and nitrosylated proteins are significantly correlated with physiosomatic symptoms (Maes et al., 2012d). IgA and IgM responses to LPS of commensal bacteria are
T
significantly associated with the clinical symptoms of IBS in CFS (Maes et al., 2014b).
IP
Therefore, it was proposed that neuro-immune and neuro-oxidative pathways contribute to the
CR
onset of physiosomatic symptoms in some psychiatric and medical disorders (Anderson et al., 2014).
US
We discovered that the physiosomatic symptoms, which emerge during pregnancy,
AN
namely chronic fatigue, back pain, muscle cramps, muscle pain, dyspepsia and gastro-intestinal symptoms, are strongly associated with IO&NS processes. Importantly, there is a strong
M
association between physiosomatic symptoms and severity of prenatal depressive symptoms,
ED
while the severity of postpartum depressive symptoms is strongly predicted by physiosomatic symptoms at the end of term. This extends our previous results that in depression and
PT
schizophrenia, depressive symptoms are strongly associated with physiosomatic symptoms
CE
(Kanchanatawan et al., 2017; Maes, 2009). These results also indicate that perinatal depressive and physiosomatic symptoms at the end of term share underlying pathways.
AC
Both zinc (inversely) and CRP (positively) levels at the end of term were significantly associated with the severity of physiosomatic and depressive symptoms, while severity of postpartum depressive symptoms was predicted by all those factors together, namely prenatal depressive and
physiosomatic symptoms coupled with lower zinc and increased CRP
(Roomruangwong et al., 2017c). We also detected significant associations between increased AOPP and NOx (positively) and -SH (inversely) and physiosomatic and prenatal depressive
ACCEPTED MANUSCRIPT 29
symptoms (Roomruangwong et al., in press). Moreover, both depressive and physiosomatic symptoms
were
inversely
associated
with
increased
IgM-mediated
natural autoimmune
responses to MDA and NO-adducts, indicating that these types of autoimmune responses are regulatory
thereby
attenuating
immune-inflammatory
processes
and
protecting
against
T
inflammation and O&NS-induced physiosomatic symptoms (Roomruangwong et al., submitted).
CR
inflammatory and O&NS pathways (Anderson et al., 2012).
IP
Such findings substantiate the theory that physiosomatic symptoms are mediated by immune-
Nevertheless, there are also pathways, which are related to end of term physiosomatic
US
symptoms, but not to prenatal depressive symptoms. Thus, physiosomatic symptoms were
AN
significantly associated with IgM responses to Klebsiella pneumonia, indicating that Gramnegative bacteria may play a role in the onset of physiosomatic symptoms (Roomruangwong et
M
al., 2017a). This is in agreement with our previous reports in major depression and CFS that
ED
increased translocation of Gram-negative bacteria is associated with the onset of physiosomatic symptoms (Maes et al., 2008b; Maes et al., 2007). Moreover, the severity of physiosomatic
PT
symptoms was positively associated with IgM responses to quinolinic acid and negatively with
CE
anthranilic acid and tryptophan, while prenatal depression was accompanied by lowered IgA
AC
responses to anthranilic acid (Roomruangwong et al., 2017 ).
5. Comparing perinatal and postpartum depression with major depression Table 2 summarizes the findings of the present review with regard to the IO&NS pathways and compares the results in non-pregnancy related major depression with those in perinatal and
postpartum depression.
While pro-inflammatory cytokines are consistently
increased in major depression (Dowlati et al., 2010; Haapakoski et al., 2015; Hiles et al., 2012;
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Howren et al., 2009; Köhler et al., 2017a; Liu et al., 2012; Valkanova et al., 2013) and bipolar disorder (Modabbernia et al., 2013; Munkholm et al., 2013), no such consistent changes are found in perinatal depression, with some studies showing no significant associations and other studies showing decreased levels of pro- and anti-inflammatory cytokines as well as neurotrophic
T
cytokines. Nevertheless, there are some data that increased IL-1 and IL-6 trans-signaling may be
IP
associated with puerperal blues. While lowered CC16 and omega-3 PUFA levels at the end of
CR
term are associated with postpartum depression, no association with prenatal depressive symptoms could be found. CRP, an immune-inflammatory marker and acute phase protein, is
US
increased, while zinc is decreased in prenatal, postpartum and non-pregnancy major depression.
AN
There is a paucity of evidence pertaining to TRYCAT pathway activation in prenatal depression, although lowered levels of plasma tryptophan and increased plasma kynurenine may
M
be associated with puerperal blues, but not postpartum depression. Also, lowered anthranilic acid
ED
is associated with both prenatal and postpartum depression, but not major depression. Activation of the TRYCAT pathway is associated with physiosomatic symptoms at the end of term rather
PT
than with prenatal depressive symptoms, while TRYCAT pathway activation is also associated
CE
with physiosomatic symptoms in major depression rather than with depression per se. Major depression and prenatal depression are both accompanied by changes in O&NS
AC
pathways, including increased levels of AOPPs and lowered levels of antioxidants, such as zinc, -SH groups and TRAP. Nevertheless, a first significant difference is that while major depression is associated with increased peroxide levels, lowered peroxide levels are found in prenatal depression. This may indicate that protein oxidation is more specific to prenatal depression than lipid peroxidation. A second difference is that while mood disorders are accompanied by lowered PON1 activities, no such changes are found in prenatal depression. While IgM autoimmune
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responses directed to MDA and NO-adducts are increased in major depression, they are inversely associated with the severity of prenatal depressive symptoms. Finally, while increased bacterial translocation is a hallmark of major depression, no such changes are found in prenatal depression.
T
While most findings reported here await further replication, a clear pattern emerged
IP
indicating activated IO&NS pathways in prenatal depression. A caveat to all these conclusions is
CR
however required. Many of these studies have a small sample size and are methodologically diverse with a large numbers of comparisons increasing the risk of false positive and negative
US
conclusions. Future research should investigate these and other IO&NS pathways including
AN
omics-based biomarkers.
M
6. Conclusions: A new model of perinatal depression
ED
Figure 2 summarizes the biomarker findings and pathways in prenatal and postpartum depression. Pregnancy-specific changes comprise immune activation as indicated by increased
PT
C-reactive protein (CRP), lowered zinc, activated O&NS pathways, AOPP and nitric oxide (NO)
CE
metabolite production and lowered levels of antioxidants (anti OX), including zinc, -SH groups
AC
and total radical trapping antioxidant parameter (TRAP).
Insert Figure 2 here.
More pronounced changes in these biomarkers are associated with the onset of prenatal depressive symptoms. Pregnancy is also accompanied by lowered levels of IgM responses to oxidative specific epitopes (OSEs) including malondialdehyde (MDA). During pregnancy,
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lowered levels of IgM-mediated auto-immune responses to MDA are inversely related to increased AOPP and NOx levels, indicating that these IgM responses exert negative feedback on increased nitro-oxidative stress. Lowered IgM responses to MDA and NO-adducts are also inversely associated with the severity of prenatal depressive and physiosomatic symptoms,
T
suggesting that less negative regulation of nitro-oxidative stress is associated with these
IP
symptoms. Interestingly, pregnancy is also accompanied by lowered IgA responses to Gram-
CR
negative bacteria indicating lowered bacterial translocation, a phenomenon which may be explained by effects of increased progesterone levels decreasing gut permeability. IgA responses
US
to Gram-negative bacteria are additionally correlated with IgM responses to OSEs, suggesting
AN
that bacterial translocation may drive natural IgM-mediated autoimmune responses. While tryptophan is decreased at the end of pregnancy, TRYCAT pathway activation is
M
not associated with prenatal depression. This may be the consequence of a tight regulation of this
ED
pathway during pregnancy with many forces modulating IDO, including its induction by immune activation, cytokines and oxidative stress, and negative feedback or regulatory effects by CRP,
PT
IgM responses to OSEs and MDA, and nitrosylation.
CE
Delivery-related changes in pro-inflammatory cytokines, including increased signs of IL1 signaling and IL-6 trans-signaling, are associated with puerperal blues but probably less or not
AC
at all with prenatal depression. The acute depletion of plasma levels of LIF-R after delivery may exaggerate the inflammatory response in the early puerperium. There is some evidence that delivery-related changes in plasma tryptophan (decreasing) and kynurenine (increasing), which are both associated with immune activation in the early puerperium, are associated with puerperal blues. Some changes in anti-inflammatory biomarkers at the end of term predict later
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postpartum
depression,
including
lowered
CC16,
an
endogenous
cytokine,
and
ω3
polyunsaturated fatty acids (PUFAs), which regulate cytokine and prostaglandin production. Overall, some biomarkers of mood disorders also play also a role in prenatal depression and, consequently, these pathways may in part explain the links between lifetime histories of
oxidation
and
NOx production seem pregnancy-specific changes,
IP
protein
T
mood disorders and perinatal depression (including increased CRP and lowered zinc). Increased which when
CR
exaggerated are linked to the onset of prenatal depressive symptoms. No current data indicate which pathways underpin the link between a lifetime history of PMS and perinatal depression.
US
Postpartum depression may be the outcome of many different pathways related to lifetime mood
AN
disorders, PMS and postpartum depression, pregnancy-specific changes in IO&NS pathways, including endogenous anti-inflammatory compounds (CC16 and ω3 PUFAs) and lowered levels
M
of some antioxidants (zinc, TRAP), lowered IgM responses to MDA and other pathways that
ED
underpin the pathophysiology of prenatal depression.
PT
Authorships.
CE
CR and MM designed the study. CR conducted all data base searches. All authors contributed
AC
equally to the writing up of the paper. All authors agreed upon the final version of the paper.
Acknowledgements
This research is funded by Chulalongkorn University; Government Budget. MB is supported by a NHMRC Senior Principal Research Fellowship 1059660.
Conflict of interest
ACCEPTED MANUSCRIPT 34
The authors have no conflict of interest with any commercial or other association in connection with the submitted article.
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Figure 1. Association between prenatal and postpartum depression and how both disorders are associated with mood disorders (MOOD) and premenstrual syndrome (PMS).
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Figure 2. Biomarker findings and pathways in perinatal depression and puerperal blues. LPS = lipopolysaccharide, MDA = malondialdehyde, O&NS = oxidative / nitrosative stress, ω3 PUFA = ω3 polyunsaturated fatty acids, CC16 = Clara cell protein, CRP = C-reactive
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protein, LIF-R = leukemia inhibitory factor receptor.
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Table 1. Pregnancy-specific changes in 6 neuro-immune, neuro-oxidative and neuro-nitrosative pathways and their respective biomarkers, which may be involved in prenatal and postnatal depression
Pathways
Relevant biomarkers as
Pregnancy-specific changes
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assessed in
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perinatal depression
Pregnancy: new set point between inflammatory
Haptoglobin,
and anti-inflammatory mechanisms
zinc
Early puerperium: a more pro-inflammatory state
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C-reactive protein,
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1. Neuro-immune
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research
with decreased anti-inflammatory potential
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Chemokines
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Cytokines
CC16 (uteroglobulin)
Tryptophan, TRYCATs
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2. Tryptophan
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LIF-receptor
IgA and IgM responses
Early puerperium further increase in immune-
directed to the TRYCAT
stimulated TRYCAT pathway activity
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catabolite
Pregnancy: TRYCAT pathway activity is enhanced
pathway
3. Neuro-oxidative
AOPP Zinc, TRAP, SH-groups
Pregnancy: activated neuro-oxidative pathways with elevated protein oxidation at the expense of lowered peroxide levels, and lowered antioxidant
Omega-3 polyunsatutared
levels, including zinc and omega-3 polyunsaturated
fatty acids
fatty acids
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4. Neuro-nitrosative
NOx production
Pregnancy: increased NO production, but no changes in nitration or nitrosylation of proteins
5. Gut-immune-
IgA/IgM responses to
Pregnancy: lowered indices of bacterial
brain
antigens/LPS of Gram-
translocation and thus increased protection against
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estrogen levels
Microbiome
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negative commensal bacteria leaky gut, probably by increased progesterone and
IgM responses to MDA and
Pregnancy: lowered IgM responses to MDA,
autoimmune
other oxidative specific
reflecting attenuated regulatory responses thereby
epitopes
contributing to activated neuro-oxidative and
IgM responses to MDA and NO may negatively
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LIF: leukemia inhibitory factor
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adducts
TRYCATs: tryptophan catabolites
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AOPP: advanced oxidation protein products
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TRAP: total radical trapping antioxidant potential NOx: nitric oxide metabolites MDA: malondiadehyde
neuro-nitrosative pathways
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IgM responses to NO-
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6. Natural
regulate depressive symptoms
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Biomarkers
Major depression
Prenatal depression
Postpartum
↑
↓-
-
↓
Neurotrophic cytokines
-
CC16
↓
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depression
CRP
↑
Zinc
↓
ω3 PUFA Tryptophan
Pro-inflammatory
Anti-inflammatory cytokines
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cytokines
-
↓
↓
↑
↑
↓
↓
↓
?
↓
↓
?
↓ in postpartum blues
Kynurenine
↓
-
↓
Anthranilic acid
↓
↓
?
IDO activity
↑ physiosomatic
↑Physiosomatic
↑ in postpartum blues
symptoms
symptoms
Lipid peroxidation
↑
↓
?
TRAP
↓
↓
?
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availability
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-
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-
?
Protein oxidation
↑
↑
↑
IgM directed to MDA
↑
↓
-
NO metabolites
↑
↑
-
IgM directed to NO-
↑
↓
-
↑
↓ in pregnancy
Translocation Gram-
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adducts
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PON1
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bacteria
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CC16: uteroglobulin CRP: C-reactive protein
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IDO: indoleamine-2,3-dioxygenase
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TRAP: total radical trapping plasma antioxidant parameter
MDA: malondialdehyde
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NO: nitric oxide or nitroso
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PON: paraoxonase
Shown in bold: pathways or compounds that are shared among non-pregnancy related major depression
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and perinatal depression
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Highlights
Postpartum depression is predicted by end of term prenatal depression (pnd)
Activated neuro-immune pathways are associated with pnd
Neuro-oxidative pathways and lowered antioxidant levels are associated with pnd
Neuro-nitrosative stress pathways with increased nitric oxide are linked to pnd
Protein oxidation and lowered zinc are the most important biomarkers of pnd.
Lowered natural IgM-mediated autoimmune responses in pregnancy are involved in pnd
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Chutima Roomruangwong, George Anderson, Michael Berk, Drozdstoy Stoyanov, André F. Carvalho, Michael Maes PII: DOI: Reference:
S0278-5846(17)30625-5 doi: 10.1016/j.pnpbp.2017.09.015 PNP 9229
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
31 July 2017 12 September 2017 17 September 2017
Please cite this article as: Chutima Roomruangwong, George Anderson, Michael Berk, Drozdstoy Stoyanov, André F. Carvalho, Michael Maes , A neuro-immune, neurooxidative and neuro-nitrosative model of prenatal and postpartum depression. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/j.pnpbp.2017.09.015
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A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression
Chutima Roomruangwong a, George Anderson b, Michael Berk
, Drozdstoy Stoyanov e, André
a,c,e
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F. Carvalho f, Michael Maes
c,d
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
b
CRC, Scotland and London, UK
c
Impact Strategic Research Center, Deakin University, Geelong, Australia
d
Orygen, the National Centre of Excellence in Youth Mental Health and Orygen Research
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e
Medical University of Plovdiv, Department of Psychiatry and Medical Psychology, Technology
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Center for Emergency Medicine
Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of
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f
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a
words: depression, cytokines, inflammation, leaky gut, autoimmune, oxidative and
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Key
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Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
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nitrosative
Corresponding author:
Prof. Dr. Michael Maes, M.D., Ph.D. IMPACT Strategic Research Centre, School of Medicine Deakin University,
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PO Box 281 Geelong 3220 Australia [email protected]
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https://scholar.google.com.br/citations?user=1wzMZ7UAAAAJ&hl=pt-BR&oi=ao
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Abstract A large body of evidence indicates that major affective disorders are accompanied by activated
neuro-immune,
neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways.
Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a
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lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum
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depression. This review provides a critical appraisal of available evidence linking IO&NS
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pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including
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perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan
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catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including
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increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites,
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lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-
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inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the
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pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do
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not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression.
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Key
words: depression, cytokines, inflammation, leaky gut, autoimmune, oxidative and
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AN
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nitrosative
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1. Introduction 1.1. Introduction to mood disorders There is considerable evidence that major depression and bipolar disorder are both accompanied by activated neuro-immune pathways (Berk et al., 2011; Berk et al., 2013; Maes,
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1995). Several meta-analyses have shown higher levels of inflammatory biomarkers, including;
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interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and IL-1β, the soluble IL-2 receptor,
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the IL-1 receptor antagonist (IL-1ra), and C-reactive protein (CRP) in patients with major depressive disorder when compared with non-depressed controls (Dowlati et al., 2010; Howren
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et al., 2009; Köhler et al., 2017a; Köhler et al., 2017b; Liu et al., 2012). A recent meta-analysis
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also shows that serum zinc, a negative acute phase reactant and immune-inflammatory biomarker, is significantly decreased in major depressive disorder (Swardfager et al., 2013). nitro-oxidative
or
nitrosative
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Increased
damage
to
proteins,
lipids,
DNA
and
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mitochondria indicates that activated neuro-oxidative and neuro-nitrosative pathways play a key role in major depressive disorder and bipolar disorder (Berk et al., 2011; Maes et al., 2011a).
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Recently, two new pathways related to the activation of neuro-immune, neuro-oxidative and
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neuro-nitrosative stress (IO&NS) pathways were discovered in major depression. Firstly, depression is accompanied by disorders of the gut-brain axis (Maes et al., 2008a; Maes et al.,
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2012c; Slyepchenko et al., 2017) as exemplified by increased immunoglobulin (Ig)A/IgM responses to antigens and LPS from Gram-negative commensal gut bacteria, as a consequence of increased bacterial translocation and increased gut permeability (leaky gut) and gut-inflammation (Köhler et al., 2016; Maes et al., 2008a; Maes et al., 2012c). Secondly, major depression is also accompanied by increased IgM-mediated autoimmune responses to oxidatively damaged cell membrane lipids and nitrosylated proteins (Köhler et al., 2016).
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1.2. Introduction to prenatal and postpartum depression Recent data indicates a particular role of neuro-immune pathways in the pathophysiology of puerperal blues and postpartum depression (Anderson and Maes, 2013; Osborne and Monk,
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2013). Puerperal blues is an emotional response consisting of mood lability, crying spells,
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anxiety, irritability and insomnia occurring in the first few days following childbirth, and
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spontaneously resolving within 2 weeks. This condition is very common (40-85%) among puerperiae and therefore seen as a normal physiological response. Postpartum depression occurs
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in 10-25% of new mothers (Anderson and Maes, 2013; Brockington, 2004; Osborne and Monk,
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2013). Various risk factors for postpartum depression have been identified, including obstetric complications, such as preeclampsia, and psychosocial factors, such as stressors during
M
pregnancy, low socioeconomic status, and a poor support system (Hirst and Moutier, 2010;
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Hoedjes et al., 2011). Postpartum depression is predicted by lifetime histories of major depression, postpartum depression, bipolar disorder, premenstrual syndrome (PMS) and prenatal
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depressive symptoms at the end of term (Clout and Brown, 2015; Eberhard-Gran et al., 2014;
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Lefkovics et al., 2014; Lydsdottir et al., 2014; Roomruangwong et al., 2017 ; Roomruangwong et al., 2016b) (Dudek et al., 2014; Jaeschke et al., 2016; Rybakowski et al., 2007).
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Figure 1 shows the association between prenatal and postpartum depression and how both disorders are associated with mood disorders (MOOD) and PMS. Prenatal depression is additionally associated with pregnancy-specific changes (including changes in hormone and IO&NS pathways that develop during pregnancy), whilst postpartum depression is predicted by prenatal depressive symptoms and a lifetime history of postpartum depression as well as pregnancy- or delivery-related stressors, including cesarean section and obstetric complications.
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Insert Figure 1 here.
Most previous research has focused on the biological and clinical predictors of
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postpartum depression usually measuring the severity of postpartum depression with the
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Edinburgh Postnatal Depression Scale (EPDS) (Eberhard-Gran et al., 2014; O'Connor et al.,
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2016). Nevertheless, some pregnancy-specific changes, including lower zinc and increased Creactive protein (CRP), are strongly related to prenatal depression and may predict postpartum
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depression (Roomruangwong et al., 2017c), suggesting that the pathophysiology of postpartum
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depression may partly overlap with and be determined by that of prenatal depression (Roomruangwong et al., 2017c). In addition, pregnancy-specific changes, including alterations in status,
activation
of
the
hypothalamic-pituitary-adrenal
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hormonal
(HPA)-axis,
immune
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activation, oxidative stress and antioxidant status (see below) alter the homeostatic balance between pro-inflammatory and oxidative pathways with immune regulatory and antioxidant
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pathways. Consequently, minor shifts in this new homeostatic set point during pregnancy could
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be additional risk factors for prenatal and thus postpartum depression. However, no previous papers have addressed the impact of these different factors on the neuro-immune, neuro-
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oxidative and neuro-nitrosative (IO&NS) pathways in pregnancy and the pathophysiology of prenatal and postpartum depression. Importantly, it can be very difficult to separate the symptoms and consequences of depression from those of physiosomatic (formerly psychosomatic) symptoms, including chronic fatigue, autonomic symptoms, hyperalgesia, somatic presentations and neurocognitive disorders (Anderson et al., 2012). Recently, we reported that the physiosomatic symptoms that emerge
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during pregnancy including chronic fatigue, back pain, muscle cramps, pain, dyspepsia and gastro-intestinal symptoms, are associated with IO&NS pathways. The current article provides a critical review of available evidence on the role of IO&NS pathways in prenatal and postpartum depression. Table 1 lists the pathways discussed (and their
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most important biomarkers) during pregnancy as well as prenatal and postpartum depression.
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This table also shows their association with affective and physiosomatic symptoms. The
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pathways are: 1) neuro-immune pathways (including cytokines, immune and inflammatory biomarkers); 2) the TRYCAT pathway (including serum concentrations of tryptophan and
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TRYCATs as well as IgA/IgM responses to TRYCATs); 3) neuro-oxidative pathways (including
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lipid peroxidation, protein oxidation, lowered levels of antioxidants); 4) neuro-nitrosative pathways (including nitric-oxide production and nitrosylation of proteins); 5) gut-brain pathway
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(including IgA/IgM responses to gut bacteria); and 6) natural autoimmune pathways (including
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IgM responses to malodialdehyde (MDA) and nitrosylated proteins).
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2. Methods
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A narrative review was conducted, following a literature searching PubMed, Google scholar, Medline, and Scopus database by combining the keywords “prenatal-depression”, inflammation”,
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“immune,
“oxidative”,
“ROS”,
“RNS”,
“nitric
oxide”,
“nitrosative”,
“tryptophan”, “tryptophan catabolites”, “kynurenine”, “IDO”, “leaky gut”, “gut-brain”, and “microbiome”. We restricted the literature search to clinical studies in the English-language published between 1990 until 2017.
3. Results
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3.1. Introduction to non-pregnancy-related major affective disorders Depression is a common disorder, characterized by depressed mood, loss of interest and pleasure, disturbances in energy, sleep and appetite, physiosomatic symptoms, and cognitive deficits. In major depressive disorder, increased levels of immune-inflammatory biomarkers (e.g.
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IL-1, IL-6, TNF-α, and CRP are evident in the plasma and cerebrospinal fluid (CSF), influencing
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the progression and severity of clinical depression in different populations (Maes et al., 2011d;
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Noto et al., 2014). Immune activation may impact the pathophysiology of a meaningful subset of depression presentations as indicated by different neuro-immune pathways, which along with
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O&NS contribute to a deteriorating course of recurrent presentations, a process referred to as
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neuroprogression (Leonard and Maes, 2012; Moylan et al., 2013; Slyepchenko et al., 2016). Alterations in the serotonergic system, including a decrease in the serotonin precursor
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tryptophan have classically been linked to depression (Meltzer and Maes, 1995). Raised levels of
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pro-inflammatory cytokines drive the induction of indoleamine-2, 3-dioxogyynase (IDO), an enzyme that catalyzes the first and rate-limiting step in the TRYCAT pathway, thereby depleting
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plasma tryptophan as a precursor of serotonin (Munn and Mellor, 2013). Different TRYCATs
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have different biological effects ranging from neurotoxicity to neuroprotection, pro- to antiinflammatory, and excitatory to inhibitory including in neurons and glia (Leonard and Maes,
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2012; Maes et al., 1994b). The TRYCAT pathway can also be stimulated by cortisol, which induces tryptophan 2, 3-dioxygenase (TDO), with TDO activation contributing to tryptophan depletion. There is some evidence that the TRYCAT pathway is activated in major depression (Maes et al., 2011b; Maes et al., 2002). Major depressive disorder is also commonly accompanied by lower antioxidant levels, including total radical trapping antioxidant potential (TRAP) (Vargas et al., 2013), paraoxonase
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1 (PON1) (Moreira et al., 2017), zinc, high-density lipoprotein cholesterol and vitamin E as well as lower ω3 polyunsaturated fatty acids (ω3 PUFAs) (Maes et al., 1994a; Maes et al., 1996). These factors regulate cellular resilience to diverse oxidative insults with lowered levels increasing the susceptibility to lipid peroxidation, including from raised levels of MDA
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(Jiménez-Fernández et al., 2015; Liu et al., 2015), and protein oxidation, as indicated by an
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increase in advanced oxidation protein products (AOPP) (Gomes et al., 2017). Recently,
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increased natural IgM-mediated autoimmune responses to oxidatively modified neoepitopes or
MDA (Maes et al., 2011c; Maes et al., 2007).
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oxidative specific epitopes (OSEs) have been observed in major depressive disorder, including to
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Major depression is also accompanied by increased NO production and iNOS activity (Gałecki et al., 2012; Maes et al., 2011a). Persistent increases in NO levels when coupled with
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raised levels of superoxide (O 2−) can lead to the formation of peroxynitrite and cell damage
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(Maes, 2008; Maes et al., 2011a). In physiological conditions, reactive nitrogen species (RNS), including NO and peroxynitrite (ONOO−), are tightly regulated by intrinsic antioxidant
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mechanisms with suppressed levels of antioxidants contributing to excessive RNS and
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consequent damage to cellular membranes and/or mitochondria (Maes et al., 2011a). Persistently elevated NO levels can lead to protein nitrosylation and thereby to the formation of new NO-
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adducts (NO-neoepitopes) (Maes, 2008; Maes et al., 2012b; Maes et al., 2011a). Importantly, some of these newly formed NO-adducts can trigger autoimmune responses directed against “nitrosative specific epitopes” (NSEs), resulting in deleterious neurotoxic effects (Boullerne et al., 2002; Maes et al., 2012b; Maes et al., 2011a). Major depression without pregnancy particularly chronic depression is also accompanied by increased IgA/IgM responses to antigens and LPS from gram-negative gut bacteria, which
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accompanies increased gut permeability and gut-driven inflammation (Maes et al., 2008a; Maes et al., 2012c; Maes et al., 2011d). Increased bacterial translocation is accompanied by inflammatory responses and increased autoimmune responses to self-antigens, including lowdensity lipoprotein cholesterol and MDA, indicating that a leaky gut may induce inflammation,
3.2.1. Pregnancy-specific changes in immune pathways
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3.2. Pregnancy-specific changes in IO&NS pathways
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oxidative stress and autoimmune responses to OSEs (Maes et al., 2013).
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Pregnancy is associated with changes in immune responses thereby allowing the
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development of the fetal allograft (Galindo-Sevilla et al., 2014; Leff-Gelman et al., 2016). Pregnancy comprises three relevant immunological adaptation phases. During early pregnancy,
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an immune-inflammatory response is triggered when the blastocyst breaks through the epithelial
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lining of the uterus for implantation, followed by the trophoblast replacement of the endothelium, and vascular smooth muscle of the maternal blood vessels to provide fetal blood
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supply (Abrahams et al., 2004; Dekel et al., 2010; Mor et al., 2011). Moreover, trophoblast cells
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induce monocytes and T helper (Th)-1 cells to secrete cytokines, including IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and growth-regulated protein alpha (GRO-α) (Mor et al.,
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2011), which can then recruit immune cells to the implantation site (Abrahams et al., 2004; Mor et al., 2005). The latter process may modulate the differentiation of immune cells (Fest et al., 2007). High levels of IL-6, IL-8, and TNF-α are also secreted by endometrial cells as well as by cells of the immune system (Manaster and Mandelboim, 2010). When pregnancy progresses to the second stage, where the mother, placenta, and fetus are symbiotic, the immune system acquires a more anti-inflammatory state (Mor et al., 2011). Finally, during late pregnancy, when
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the fetus is prompt to be delivered, immune cells influx into the myometrium in order to promote an inflammatory response (Romero et al., 2006), promoting uterine contractions, birth of the baby, placental rejection and defense against puerperal sepsis (Mor et al., 2011). End of term pregnancy is accompanied by increased serum levels of IL-6, IL-1RA,
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leukemia inhibitory factor receptor (LIF-R) and increased CRP but lowered zinc levels (Maes et
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al., 2000; Roomruangwong et al., 2017c). These findings in aggregate indicate that end of term
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pregnancy is accompanied by immune activation, an inflammatory response (increased IL-6 and CRP and lowered zinc), and increased negative immunoregulatory responses (increased sIL-1RA
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and LIF-R levels). Hence, at the end of term, pregnancy is characterized by indications of
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increased peripheral inflammation, which is kept in balance by increases in immune regulatory processes. This is achieved partly via immune mechanisms as well as increased hormonal
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activities, including increased HPA-axis activity and progesterone levels (Maes et al., 2001).
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After delivery, however, there may be a breakdown in these immune dampening mechanisms as exemplified by significantly increased serum levels of IL-6, sIL-6R and sIL-1RA
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concentrations and lowered LIF-R levels in the early puerperium (Maes et al., 2001). This
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indicates that the early puerperium is characterized by increased IL-6 trans-signaling (Maes et al., 2014a) and IL-1 signaling (Maes et al., 2012e), whereas the anti-inflammatory effects of LIF-
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R (Hunt et al., 2013) levels are sharply reduced. All in all, while pregnancy is characterized by a new balance between inflammatory and anti-inflammatory mechanisms, the early puerperium appears to be accompanied by a more pro-inflammatory state.
3.2.2. Pregnancy-specific changes in TRYCAT pathway activity
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Maternal total tryptophan is elevated in early pregnancy and returns to slightly below normal during mid-gestation, and decreases again by 25% during late pregnancy (Schröcksnadel et al., 1996). TDO activity is lowered during early to mid-pregnancy, but enhanced in late pregnancy. TDO is induced by glucocorticoids whilst inhibited by estrogen and progesterone
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(Badawy, 1988). TDO mRNA expression in the decidualized endometrium is increased around
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the implanted embryo, suggesting its involvement in the implantation process through the
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regulation of tryptophan levels at the implantation site (Tatsumi et al., 2000). IDO is highly present in significant amounts in the placenta (Kudo et al., 2004; Ligam et al., 2005;
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Manuelpillai et al., 2005; Yamazaki et al., 1985). Placental IDO, kynureninase and 3-
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hydroxyanthranilic acid oxidase activity may be enhanced by cytokines (e.g. IFN-γ), which may be released in response to infection and inflammation. Placental IDO is suppressed by
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progesterone, especially during decidualization (Kudo et al., 2004). There is evidence suggesting
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that during early to mid-pregnancy, tryptophan degradation occurs mainly via TDO, whereas IDO may become more important during mid- to late pregnancy (Badawy, 2015; Kudo et al.,
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2004; Ligam et al., 2005).
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Maternal plasma tryptophan is significantly decreased at the end of term and further reduced in the days after delivery. This indicates IDO induction at the end of term with further
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stimulation after delivery through immune activation (Maes et al., 2001). Moreover, in pregnant women at the end of term, the kynurenine/tryptophan (K/T) quotient (indicating IDO activity) is significantly increased, while the K/T quotient further increases in the early puerperium in association with immune activation and enhanced inflammatory responses (Maes et al., 2002). This shows that IDO activity is enhanced at the end of pregnancy and further increases in early puerperium and that this phenomenon is partly immune- mediated.
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3.2.3. Pregnancy-specific changes in O&NS pathways In normal pregnancy, there is an increase in nitro-oxidative processes (Ardalić et al., 2014; Ferguson et al., 2015; Mihu et al., 2012), characterized by a transient increase in the
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production of reactive oxygen species (ROS), which is partially counterbalanced by an increase
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in antioxidant mechanisms (Burton and Hung, 2003; Mihu et al., 2012). A certain amount of
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oxidative stress based redox signaling during pregnancy is necessary for embryonic and fetal growth (Dennery, 2010). A new balance between ROS and antioxidants is necessary for
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decidualization, normal fetal organogenesis and development during pregnancy (Al-Gubory et
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al., 2010; Dennery, 2004). At the end of term, significantly increased levels of AOPP and nitric oxide metabolites (NOx) coupled to a decrease in total radical trapping potential (TRAP), zinc, -
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sulfhydryl (-SH) groups and peroxides (LOOH) levels are evident (Roomruangwong et al., in
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press). These findings suggest that pregnancy is accompanied by very high levels of protein oxidation (at the expense of peroxide production) and NOx production coupled with lowered
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antioxidant activity. Moreover, during pregnancy, there are marked changes in lipid metabolism,
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characterized by significant increases in total cholesterol levels in association with increased oxidative stress (Toescu et al., 2002).
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Increased O&NS in pregnancy leads to more negative outcomes for mother and baby, e.g. due to the impairment of endothelial and vascular functions, and increased apoptotic activity in the placenta (Saad et al., 2016). Increased O&NS also raises the likelihood of the atherosclerosis and endothelial dysfunction that are observed in pre-eclampsia (Roberts and Hubel, 1999). A disturbed placental milieu with high O&NS may induce fetal programming of adult disease via increased DNA damage and mutations (Saad et al., 2016). Due to their low antioxidant content,
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fetal pancreatic β-cells are extremely vulnerable to damage by ROS (Simmons, 2006), which may lead to permanent pancreatic cell functional alterations and the onset of later diabetes (Kamel et al., 2014). Increased AOPP levels at the end of term are associated with lowered cord length and an increased risk for caesarian section, whereas lowered PON1 activity at the end of
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term is associated with increased labor duration and neonatal problems, including more night
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time awakenings and sucking problems in the early neonatal period (Roomruangwong et al., in
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press). Moreover, increased protein nitrosylation is strongly associated with specific pregnancy complications such as pre-eclampsia and gestational diabetes, whist nitrosylation may also
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disrupt normal placental functions (Lyall et al., 1998; Myatt, 2010). Overall, pregnancy is
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characterized by increased protein oxidation and NO production coupled to lowered levels of key
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antioxidants, including zinc.
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3.2.4. Pregnancy-specific changes in bacterial translocation Adaptation of the gastrointestinal tract, e.g. increased size of villus, increased intestinal
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motility and transit time, is important during pregnancy to ensure the maintenance of high
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metabolic demands of the developing fetus (Astbury et al., 2015). Moreover, there are changes in the gut microbiome during pregnancy (Koren et al., 2012), including decreased microbial alpha
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diversity (types of sequences in each sample) and an increase in beta diversity (distribution of different types among samples) (Turnbaugh et al., 2006), with increased amounts of bacteria species capable of sugar fermentation (e.g. Firmicutes species) (Koren et al., 2012). There is also an increased population of Lactobacillus, Streptococcus, Enterococcus, and Proteobacteria during the third trimester of pregnancy (Koren et al., 2012; Mukhopadhya et al., 2012; Turnbaugh et al., 2006). Moreover, estrogen may increase gut permeability and proliferation of
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gram-negative bacteria in the gut which if undefended can lead to portal endotoxemia (Farhat et al., 1996). Studies demonstrate an association of LPS exposure and increased maternal serum corticosterone, IL-1β levels, injury to placental tissue and increased rate of pregnancy loss (Kirsten et al., 2013; Pontillo et al., 2013).
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Pregnancy is accompanied by lowered translocation of Gram-negative bacteria and thus
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lowered gut permeability as indicated by significantly decreased levels of IgA responses to
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Gram-negative bacteria, suggesting that pregnant women could be protected against the development of a ‘leaky’ gut (Roomruangwong et al., 2017a). In this respect, in vitro and
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preclinical studies show that estrogen may induce a 2-8 fold increase in intestinal mucus
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viscosity resulting in decreased gut permeability (Braniste et al., 2009; Diebel et al., 2015; Doucet et al., 2010; Looijer-van Langen et al., 2011). Treatment with progesterone may increase
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mucus level production in the duodenum and attenuate mucosal injury and microvascular
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leakage (Drago et al., 1999). Therefore, it may be suggested that pregnant women may be protected against leaky gut by increased progesterone and maybe increased estrogen levels
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(Roomruangwong et al., 2017a).
3.2.5. Pregnancy-specific changes in autoimmune responses autoimmune
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Many
diseases
characteristically
flare
up
during
early
pregnancy
(implantation) and perinatal periods, and may recur upon subsequent pregnancies (Amino et al., 1999; Gleicher, 2007; Ruiz-Irastorza et al., 1996; Schramm et al., 2006; Sliwa et al., 2006), including thyroid disease, autoimmune hepatitis and systemic lupus erythematosus. Subclinical autoimmunity has been shown to be associated with recurrent pregnancy loss (Dudley and Branch, 1991; Gleicher et al., 1993; Perricone et al., 2012). Pregnancy is also associated with a
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shift toward a T helper (Th)-2 type immune response (Mor et al., 2011) and increased IgM levels in pregnant animal models (Muzzio et al., 2014), while studies on autoantibody levels in pregnant women have yielded conflicting results (D’Armiento et al., 1980; Farnam et al., 1984; Levy, 1982; Mavridis et al., 1992) with variability depending on the type of autoimmune
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responses assessed.
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At the end of term attenuated natural IgM-mediated responses to OSEs, including MDA,
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have been found indicating a suppression of this part of the compensatory anti- inflammatory reflex system (CIRS), which is an adaptive anti-inflammatory response of the immune system
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that attenuates an excessive inflammatory response caused by pathogens or immune trauma
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(Maes et al., 2012a; Roomruangwong et al., 2017b). Moreover, at the end of term, IgM responses to OSEs were significantly correlated with IgM and IgA responses to Gram-negative commensal
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bacteria, including Citrobacter koseri, Klebsiella pneumoniae and Morganella morganii
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(Roomruangwong et al., 2017a). This could indicate that the lowered IgM responses to OSEs at the end of pregnancy are in part attributable to lowered bacterial translocation.
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Most importantly, at the end of term, we found an inverse relationships between IgM
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responses to MDA, on the one hand, and O&NS biomarkers (AOPP and NOx and diverse indices of increased nitro-oxidative potential), on the other (Roomruangwong et al., submitted).
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These results provide initial evidence that natural autoimmune responses to MDA exert protective effects attenuating O&NS pathways via immune dampening and anti-oxidant effects. Moreover, the lowered natural autoimmune responses at the end of pregnancy could reflect attenuated regulatory responses thereby contributing to increased IO&NS pathways and maybe increased autoimmune potential during pregnancy (Frostegård, 2013; Rahman et al., 2016;
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Roomruangwong et al., 2017b). Table 1 (right column) summarizes the pregnancy-specific changes in the 6 different IO&NS pathways.
4. IO&NS Pathways in prenatal depression
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4.1. Neuro-immune pathways in prenatal depression
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In the early puerperium increased levels of IL-6 and IL-6R concentrations are associated
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with increased self-reported levels of depression, while increased serum IL-6 and IL-1RA coupled with lowered LIF-R levels, are associated with self-reported anxiety (Maes et al., 2000).
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These findings suggest that increased IL-6 trans-signaling is associated with depressive
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symptoms in the early puerperium and increased inflammatory and IL-1 signaling may be associated with anxiety symptoms. However, the common self-reported anxiety and depression
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in the days after delivery mostly indicate puerperial blues rather than postpartum depression.
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Moreover, we were unable to detect any significant associations between these inflammatory changes in the early puerperium and postpartum depression within the first few months after
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delivery. Interestingly, in the early puerperium sIL-1RA levels are significantly higher in
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primiparae as compared with multiparae (Maes et al., 2004), suggesting that parity may modulate IL-1 signaling following delivery.
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Other studies during the prenatal period yielded mixed results (Azar and Mercer, 2013; Blackmore et al., 2011; Cassidy-Bushrow et al., 2012; Christian et al., 2009; D’Anna et al., 2011; Maes et al., 2000). Previous work suggested that some inflammation-related pregnancy morbidities, including pre-eclampsia, preterm birth and gestational diabetes, are associated with prenatal depression (Alder et al., 2007; Kharaghani et al., 2012; Kozhimannil et al., 2009; Kurki et al., 2000; Orr et al., 2002). Moreover, studies in specific populations (e.g. African American,
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and those with high body mass index (BMI)) found an increased rate of prenatal depression in association with increased levels of IL-6 (Blackmore et al., 2014) and adverse obstetric outcomes, including pre-eclampsia, low birth weight and premature ruptured of the membranes (PROM) (Gomez et al., 1995; Saito, 2000; Santhanam et al., 1991). Karlsson et al. observed that
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IL-12, IL-9 and IL-13, and higher IFN/IL-4 ratio and IL-5 correlated positively with depressive
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symptoms, whereas IL-6 and TNF-α were not related to prenatal symptoms (Karlsson et al.,
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2017). Leff-Gelman et al. proposed that the same immune-inflammatory processes involved in
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major depression operate in the placenta during perinatal depression. Thus, activation of TollLike Receptor (TLR)2 and TLR4 in placental immune cells could promote a shift towards a
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Th1/Th17 bias with increased production of pro-inflammatory cytokines triggering depressive symptoms (Leff-Gelman et al., 2016). Higher CRP levels at the end of term are strongly
M
associated with severity of prenatal depressive symptoms, indicating that when pregnancy-
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related inflammation increases, depressive symptoms may emerge at the end of term
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(Roomruangwong et al., 2017c).
However, recent studies also found inverse associations between prenatal depressive
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scores and levels of inflammatory markers. In a pilot study, Shelton et al. observed that prenatal
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depressive symptoms were inversely associated with IL-1, TNF-α and IL-17 (Shelton et al., 2015). Edvinsson et al. (Edvinsson et al., 2017) reported that inflammatory markers were downregulated in prenatal depression, for example macrophage colony-stimulating factor, TNFrelated apoptosis inducing ligand and fractalkine. All in all, these results suggest that proinflammatory cytokines may be less involved in the pathophysiology of prenatal depression as compared to non-pregnant mood disorders.
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The HPA-axis may be a potential mediator between prenatal depression and the inflammatory response (Horowitz et al., 2013; Sun et al., 2011). During pregnancy, cortisol output is increased while the HPA-axis is less reactive to glucocorticoid feedback (Maes et al., 1992). The majority of maternal cortisol is converted to an inactive form (cortisone) by the
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enzyme 11-beta hydroxysteroid dehydrogenase (11 β -HSD) (Murphy et al., 1974), and there is
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evidence that the 11β-HSD1 enzyme activity may be higher in M2 than in M1 macrophages
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(Chinetti-Gbaguidi et al., 2012). There is a negative correlation between those inflammatory markers and cortisone levels in healthy pregnant women but not in women with prenatal
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depression (Hellgren et al., 2013; Horowitz et al., 2013). These findings suggest that prenatal
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depression may be associated with an incomplete switch from a predominant M2 to M1 phenotype with connections between HPA-axis dysregulation, inflammation, and prenatal
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depression (Brown et al., 2014). In this respect, Gelman et al proposed that dysfunctions of the
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the fetus (Gelman et al., 2015).
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HPA-axis may be caused by immune and placental factors leading to cortisol-induced toxicity to
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4.2. The TRYCAT pathway in prenatal depression In the early puerperium, an inverse association was detected between lowered L-
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tryptophan levels and self-reported depressive and anxiety symptoms, indicating that lowered availability of L-tryptophan to the brain is associated with puerperal blues (Maes et al., 1992). Nevertheless, a follow-up study showed that the lowered availability of plasma tryptophan to the brain in the early puerperium, which is in part mediated by inflammatory processes, is not related to either indicants of post-partum blues or postpartum depression arising some months later (Maes et al., 2001). More importantly, the increases in plasma kynurenine and the K/T quotient
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from the end of term and early puerperium (which are both related to immune activation) were significantly associated with indices of puerperal depressive and anxiety blues but not with later postpartum depression (Maes et al., 2002). All in all, these results provide evidence that an increased catabolism of tryptophan into kynurenine arising from immune activation in the early
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puerperium, may be related to puerperal blues, but not postpartum depression. Bailara et al.
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(Baïlara et al., 2006) reported that a lowered availability of L-tryptophan to the brain as a
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consequence of changes in competing amino acids partly accounts for puerperal blues. Veen et al. reported that increased L-tryptophan breakdown and increased kynurenine levels in the
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postpartum period do not occur in women with postpartum depression and that kynurenine is
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significantly lower in patients with postpartum depression (Veen et al., 2016). Using a new assay to measure TRYCAT pathway activity (namely IgA and IgM
M
responses to TRYCATs) we could not verify that TRYCAT pathway activity at the end of term
ED
is associated with prenatal depression or postpartum depressive symptoms. TRYCAT pathway activation was significantly associated with a lifetime history of PMS rather than with prenatal
PT
depression or a lifetime history of depression. Nevertheless, lowered IgA responses to anthranilic
CE
acid were significantly associated with prenatal depression (Roomruangwong et al., 2017 ). In addition, we found that the TRYCAT pathway is tightly regulated by many different inputs, inflammatory
AC
including
signals,
nitrosative
stress,
bacterial translocation,
and
regulatory
autoimmune responses (Roomruangwong et al., 2017a; Roomruangwong et al., 2017b).
4.3. Oxidative stress and nitrosative stress in prenatal depression Recent studies showed that oxidative parameters, namely MDA, superoxide dismutase, catalase, total antioxidant status, total oxidant status, and oxidative stress index levels in the fetal
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cord blood of depressed mothers were not significantly different from healthy pregnant controls, suggesting that the placental barrier may protect against oxidative stress (Camkurt et al., 2017; Camkurt et al., 2016b). However, another study performed on fetal cord blood reported decreased levels of glutathione peroxidase among prenatally depressed versus control mothers
glutathione peroxidase levels in the fetal circulation may reflect inadequate
IP
Decreased
T
without significant changes in the antioxidant enzyme myeloperoxidase (Camkurt et al., 2016a).
CR
compensation for oxidative activity in prenatal depression, resulting in an oxidative intrauterine environment, leading to disturbances in fetal brain development and plasticity (Camkurt et al.,
US
2016a). Prenatal depression has also been demonstrated to be a risk factor for cardiovascular
AN
diseases during pregnancy putatively via activation of oxidative stress and immune-inflammatory pathways (Kurki et al., 2000; Nicholson et al., 2016).
M
Recently, a significant association was found between increased O&NS, lowered
ED
antioxidant (namely: –SH groups, zinc, TRAP) and LOOH levels and prenatal depressive symptoms (Roomruangwong et al., in press). The most important indicators of O&NS associated
PT
with prenatal depression were increased AOPP and NOx, indicating protein oxidation and
CE
increased NO production leading to nitrosative and nitro-oxidative stress. The inverse association between lowered levels of –SH groups and prenatal depressive symptoms may be explained by
AC
increased use of –SH groups for nitrosothiol (SNO) synthesis, while the inverse association between peroxides and depressive symptoms may be explained by increased use of peroxides during AOPP synthesis and inhibition of peroxides by AOPP (Bordignon et al., 2014; Piwowar, 2010). This suggests that prenatal depression is associated with protein oxidation rather than lipid peroxidation (Roomruangwong et al., in press). The inverse association between TRAP and prenatal depression may indicate that lowered antioxidant defenses are associated with the onset
ACCEPTED MANUSCRIPT 23
of depressive symptoms at the end of term. Moreover, end of term serum zinc was strongly and inversely associated with prenatal depressive symptoms. Thus, increased protein oxidation and NOx production, lowered production of peroxides and lowered antioxidant defenses occur in normal pregnancy, but when protein oxidation and/or NOx production further increase or when
T
antioxidant levels further decrease depressive symptoms may emerge. All in all, these findings
IP
indicate that pregnancy-associated activation of protein oxidation and NO pathways are
CR
associated with the onset of depressive symptoms at the end of term (Roomruangwong et al.,
US
2017d).
AN
4.4. Bacterial translocation in prenatal depression
As discussed in section 3.2.3., pregnant women show significantly lowered IgA
M
responses to Gram-negative bacteria, indicating lowered bacterial translocation. In addition, in
ED
pregnant women, there is a lack of significant associations between IgA/IgM responses to Gramnegative bacteria and prenatal depression (Roomruangwong et al., 2017a). These negative
PT
findings contradict the findings in major depression indicating increased gut permeability (Berk
CE
et al., 2013; Bested et al., 2013; Logan, 2015; Logan et al., 2016; Maes et al., 2008a; MartinSubero et al., 2016; Naseribafrouei et al., 2014; Slyepchenko et al., 2016). Nevertheless, in the
AC
same study, we found that higher IgA/IgM responses to Gram-negative bacteria are associated with increased levels of haptoglobin and TRYCATs, especially quinolinic acid and the quinolinic acid / kynurenic acid ratio (indicating neurotoxic potential), suggesting that increased bacterial translocation may induce immune-inflammatory responses and TRYCAT pathway activation thereby increasing neurotoxic potential. It should be stressed however that these phenomena are not related to prenatal depression. In conclusion, our findings suggest that
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pregnancy may protect against bacterial translocation, and that end of term mucosa-derived immune responses to Gram-negative bacteria may contribute to immune activation.
4.5. Natural autoimmune IgM responses to MDA / NO-adducts in prenatal depression
T
Pregnant women show increased thyroperoxidase antibodies, which are significantly
IP
associated with prenatal depression at 12 weeks gestation and at 4 and 12 weeks postpartum
CR
(Kuijpens et al., 2001). Another study, however, did not find a significant association between prenatal depression and increased IgM levels, although there were higher levels of IgG among
US
pregnant women with major depression than those with minor depression (Kianbakht et al.,
AN
2013). All in all, there is no clear evidence that common autoimmune responses may underpin perinatal depressive episodes.
M
At the end of term, the IgM responses directed against MDA were inversely associated
ED
with prenatal depressive symptoms (Roomruangwong et al., submitted). IgM response to MDA are natural regulatory autoimmune responses which help to clear debris, for example oxidatively
PT
damaged and dying or apoptotic cells expressing MDA (Maes et al., 2011a; Maes et al., 2011c;
CE
Tsuboi et al., 2013; Zheng et al., 2013). As such, these natural IgM antibodies target OSEs, thereby attenuating immune-inflammatory responses. Therefore, lowered IgM responses to
AC
MDA at the end of term are probably accompanied by lowered feedback on AOPP and NOx production and thus increased protein oxidation and nitrosylation leading to more antenatal depressive symptoms. Interestingly, IgM responses to NO-adducts were significantly and positively related to increased NOx levels indicating that measurements of IgM responses to NO-adducts reflect increased NO production and nitrosylation. In addition, IgM responses to NO-adducts were not
ACCEPTED MANUSCRIPT 25
only positively associated with a life time history of mood disorders, but also inversely with prenatal depressive symptoms (Roomruangwong et al., 2017b). This indicates that increased nitrosylation may be a trait marker of depression and bipolar disorder, and that increased autoimmune responses to NO adducts may be protective against prenatal depressive symptoms.
T
The IgM responses to NO-cysteinyl were significantly higher in women with a lifetime history of
IP
depression and therefore may possibly act as a trait marker of depression (Roomruangwong et
CR
al., 2017b). Thus, the pathophysiology of prenatal depression differs significantly from that of major depression with respect to increased nitrosylation and ensuing autoimmune responses to
US
NO-adducts. Overall, natural IgM responses to MDA and NO-adducts may be protective by
AN
attenuating nitro-oxidative pathways or depressive symptoms.
M
4.6. Do the biomarkers at the end of term predict postnatal depression?
ED
Since prenatal depression is the single best predictor of postpartum depression and since the latter is also predicted by lifetime histories of mood disorders, PMS and postpartum
PT
depression, it may be posited that the pathophysiology of postpartum depression is to a large
CE
extent related to that of prenatal depression, mood disorders and PMS (Roomruangwong et al., 2017 ; Roomruangwong et al., 2016b). In addition, the postnatal period is a period of bodily
AC
system stabilization back to the pre-pregnant state. This is a period where an accelerated immune-inflammatory response during labor continues into the early puerperium, while being mediated through both pro- and anti-inflammatory mediators for healing and involution (NilsenHamilton et al., 2003; Sennstrom et al., 2000). Finally, psychological stressors and exogenous stressors related to pregnancy and delivery (e.g. caesarian section, unwanted pregnancy, marital stress) may further enhance the activated IO&NS pathways in the early postnatal period.
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There is some evidence that immune changes at the end of pregnancy may predict postpartum depression. Thus, lowered levels of Clara cell protein (CC16), an endogenous antiinflammatory compound, are associated with postpartum depression some weeks later (Maes et al., 2000; Maes et al., 1999). Lowered levels of ω3 polyunsaturated fatty acids (PUFAs) at the
T
end of term predict postpartum depression some weeks later (De Vriese et al., 2003). ω3 PUFAs
IP
have anti-inflammatory effects by attenuating the activities of pro-inflammatory cytokines and
CR
therefore lowered ω3 PUFAs at the end of term may contribute to an overall increase in peripheral inflammation (De Vriese et al., 2003). Other end of term predictors of postpartum
US
depression include increased CRP, hematocrit, AOPP and NOx as well as lower zinc levels
AN
(Roomruangwong et al., 2017b; Roomruangwong et al., 2016a; Roomruangwong et al., 2017c). Interestingly, some of these biomarkers are also markers of prenatal depression (namely CRP,
M
zinc, AOPP, NOx), whereas other are not associated with prenatal depression (increased
ED
hematocrit). It is hypothesized that disorders in the crosstalk between the immune system and the HPA-axis may be associated with the onset of postpartum depression (Corwin and Pajer, 2008).
PT
There are now more reports on immune-inflammatory biomarkers during pregnancy
CE
predicting postpartum depression. IL-6 is one of the most frequent investigated inflammatory biomarkers showing a significant association with postpartum depression in some (Osborne and
AC
Monk, 2013), but not all studies (Maes et al., 2011d; Skalkidou et al., 2009). In another study, lowered levels of TNF- were associated with later postpartum depression (Corwin et al., 2015). Prenatal neopterin levels and pre- and post-natal T regulatory cells are increased in women who later developed postpartum depression (Krause et al., 2014). Accortt et al. (2015) were unable to detect associations between IL-6 and IL-10 and their ratio and depression scores (Accortt et al., 2016). IL-6 and IFN- were associated with postpartum depression in one study (Tsao et al.,
ACCEPTED MANUSCRIPT 27
2006), but not in another (Bränn et al., 2017). Nevertheless, the latter study reported that lowered levels of immune biomarkers (both pro- and anti-inflammatory) in late pregnancy predict postpartum depression, including signal transducing adaptor molecule- binding protein (STAMBP), AXIN-1, adenosine deaminase (ADA), sulfotransferase 1A1 (ST1A1), and IL-10 (Bränn et
T
al., 2017). STAM-BP is a zinc-metalloprotease, which is involved in cytokine-mediated
IP
intracellular signal transduction and cell growth (Suzuki et al., 2011). ADA is a dipeptidyl
CR
peptidase-4 (DPP IV) binding protein, which regulates T cell activation (Gines et al., 2002). Interestingly, DPP IV is significantly decreased in patients with non-pregnant major depression
US
(Maes et al., 1991). AXIN1 mediates cell growth, apoptosis and development and functions as a
AN
scaffold protein in TGF- signaling (Liu et al., 2006; Ye et al., 2015), while IL-10 functions as a regulatory cytokine with negative immunoregulatory properties with lower levels having some
M
association with suboptimal pregnancy outcomes (Sadowsky et al., 2003). ST1A1 functions as a
ED
catalyzer of sulfur conjugation for many neurotransmitters (Gamage et al., 2005). All in all, there
PT
is some evidence that prenatal depression-related changes in IO&NS pathways or IO&NS
CE
changes at the end of pregnancy may predict postpartum depression.
4.7. Physiosomatic symptoms at the end of term of pregnancy
AC
Physiosomatic symptoms such as fatigue, autonomic nervous system hyperactivity symptoms, hyperalgesia, gastro-intestinal symptoms and somatic presentations are common presentations in both psychiatric and medical disorders, including chronic fatigue syndrome (CFS) and multiple sclerosis (Morris and Maes, 2013). There is evidence of significant associations among physiosomatic symptoms in depression, CFS and somatization, and immuneinflammatory processes, including alterations in the tryptophan catabolite (TRYCAT) pathway
ACCEPTED MANUSCRIPT 28
(Anderson et al., 2012). Increased pro-inflammatory cytokine levels in depression are associated with the presence of fatigue and physiosomatic symptoms (Maes et al., 2012f). Serum IgM antibodies to OSEs and nitrosylated proteins are significantly correlated with physiosomatic symptoms (Maes et al., 2012d). IgA and IgM responses to LPS of commensal bacteria are
T
significantly associated with the clinical symptoms of IBS in CFS (Maes et al., 2014b).
IP
Therefore, it was proposed that neuro-immune and neuro-oxidative pathways contribute to the
CR
onset of physiosomatic symptoms in some psychiatric and medical disorders (Anderson et al., 2014).
US
We discovered that the physiosomatic symptoms, which emerge during pregnancy,
AN
namely chronic fatigue, back pain, muscle cramps, muscle pain, dyspepsia and gastro-intestinal symptoms, are strongly associated with IO&NS processes. Importantly, there is a strong
M
association between physiosomatic symptoms and severity of prenatal depressive symptoms,
ED
while the severity of postpartum depressive symptoms is strongly predicted by physiosomatic symptoms at the end of term. This extends our previous results that in depression and
PT
schizophrenia, depressive symptoms are strongly associated with physiosomatic symptoms
CE
(Kanchanatawan et al., 2017; Maes, 2009). These results also indicate that perinatal depressive and physiosomatic symptoms at the end of term share underlying pathways.
AC
Both zinc (inversely) and CRP (positively) levels at the end of term were significantly associated with the severity of physiosomatic and depressive symptoms, while severity of postpartum depressive symptoms was predicted by all those factors together, namely prenatal depressive and
physiosomatic symptoms coupled with lower zinc and increased CRP
(Roomruangwong et al., 2017c). We also detected significant associations between increased AOPP and NOx (positively) and -SH (inversely) and physiosomatic and prenatal depressive
ACCEPTED MANUSCRIPT 29
symptoms (Roomruangwong et al., in press). Moreover, both depressive and physiosomatic symptoms
were
inversely
associated
with
increased
IgM-mediated
natural autoimmune
responses to MDA and NO-adducts, indicating that these types of autoimmune responses are regulatory
thereby
attenuating
immune-inflammatory
processes
and
protecting
against
T
inflammation and O&NS-induced physiosomatic symptoms (Roomruangwong et al., submitted).
CR
inflammatory and O&NS pathways (Anderson et al., 2012).
IP
Such findings substantiate the theory that physiosomatic symptoms are mediated by immune-
Nevertheless, there are also pathways, which are related to end of term physiosomatic
US
symptoms, but not to prenatal depressive symptoms. Thus, physiosomatic symptoms were
AN
significantly associated with IgM responses to Klebsiella pneumonia, indicating that Gramnegative bacteria may play a role in the onset of physiosomatic symptoms (Roomruangwong et
M
al., 2017a). This is in agreement with our previous reports in major depression and CFS that
ED
increased translocation of Gram-negative bacteria is associated with the onset of physiosomatic symptoms (Maes et al., 2008b; Maes et al., 2007). Moreover, the severity of physiosomatic
PT
symptoms was positively associated with IgM responses to quinolinic acid and negatively with
CE
anthranilic acid and tryptophan, while prenatal depression was accompanied by lowered IgA
AC
responses to anthranilic acid (Roomruangwong et al., 2017 ).
5. Comparing perinatal and postpartum depression with major depression Table 2 summarizes the findings of the present review with regard to the IO&NS pathways and compares the results in non-pregnancy related major depression with those in perinatal and
postpartum depression.
While pro-inflammatory cytokines are consistently
increased in major depression (Dowlati et al., 2010; Haapakoski et al., 2015; Hiles et al., 2012;
ACCEPTED MANUSCRIPT 30
Howren et al., 2009; Köhler et al., 2017a; Liu et al., 2012; Valkanova et al., 2013) and bipolar disorder (Modabbernia et al., 2013; Munkholm et al., 2013), no such consistent changes are found in perinatal depression, with some studies showing no significant associations and other studies showing decreased levels of pro- and anti-inflammatory cytokines as well as neurotrophic
T
cytokines. Nevertheless, there are some data that increased IL-1 and IL-6 trans-signaling may be
IP
associated with puerperal blues. While lowered CC16 and omega-3 PUFA levels at the end of
CR
term are associated with postpartum depression, no association with prenatal depressive symptoms could be found. CRP, an immune-inflammatory marker and acute phase protein, is
US
increased, while zinc is decreased in prenatal, postpartum and non-pregnancy major depression.
AN
There is a paucity of evidence pertaining to TRYCAT pathway activation in prenatal depression, although lowered levels of plasma tryptophan and increased plasma kynurenine may
M
be associated with puerperal blues, but not postpartum depression. Also, lowered anthranilic acid
ED
is associated with both prenatal and postpartum depression, but not major depression. Activation of the TRYCAT pathway is associated with physiosomatic symptoms at the end of term rather
PT
than with prenatal depressive symptoms, while TRYCAT pathway activation is also associated
CE
with physiosomatic symptoms in major depression rather than with depression per se. Major depression and prenatal depression are both accompanied by changes in O&NS
AC
pathways, including increased levels of AOPPs and lowered levels of antioxidants, such as zinc, -SH groups and TRAP. Nevertheless, a first significant difference is that while major depression is associated with increased peroxide levels, lowered peroxide levels are found in prenatal depression. This may indicate that protein oxidation is more specific to prenatal depression than lipid peroxidation. A second difference is that while mood disorders are accompanied by lowered PON1 activities, no such changes are found in prenatal depression. While IgM autoimmune
ACCEPTED MANUSCRIPT 31
responses directed to MDA and NO-adducts are increased in major depression, they are inversely associated with the severity of prenatal depressive symptoms. Finally, while increased bacterial translocation is a hallmark of major depression, no such changes are found in prenatal depression.
T
While most findings reported here await further replication, a clear pattern emerged
IP
indicating activated IO&NS pathways in prenatal depression. A caveat to all these conclusions is
CR
however required. Many of these studies have a small sample size and are methodologically diverse with a large numbers of comparisons increasing the risk of false positive and negative
US
conclusions. Future research should investigate these and other IO&NS pathways including
AN
omics-based biomarkers.
M
6. Conclusions: A new model of perinatal depression
ED
Figure 2 summarizes the biomarker findings and pathways in prenatal and postpartum depression. Pregnancy-specific changes comprise immune activation as indicated by increased
PT
C-reactive protein (CRP), lowered zinc, activated O&NS pathways, AOPP and nitric oxide (NO)
CE
metabolite production and lowered levels of antioxidants (anti OX), including zinc, -SH groups
AC
and total radical trapping antioxidant parameter (TRAP).
Insert Figure 2 here.
More pronounced changes in these biomarkers are associated with the onset of prenatal depressive symptoms. Pregnancy is also accompanied by lowered levels of IgM responses to oxidative specific epitopes (OSEs) including malondialdehyde (MDA). During pregnancy,
ACCEPTED MANUSCRIPT 32
lowered levels of IgM-mediated auto-immune responses to MDA are inversely related to increased AOPP and NOx levels, indicating that these IgM responses exert negative feedback on increased nitro-oxidative stress. Lowered IgM responses to MDA and NO-adducts are also inversely associated with the severity of prenatal depressive and physiosomatic symptoms,
T
suggesting that less negative regulation of nitro-oxidative stress is associated with these
IP
symptoms. Interestingly, pregnancy is also accompanied by lowered IgA responses to Gram-
CR
negative bacteria indicating lowered bacterial translocation, a phenomenon which may be explained by effects of increased progesterone levels decreasing gut permeability. IgA responses
US
to Gram-negative bacteria are additionally correlated with IgM responses to OSEs, suggesting
AN
that bacterial translocation may drive natural IgM-mediated autoimmune responses. While tryptophan is decreased at the end of pregnancy, TRYCAT pathway activation is
M
not associated with prenatal depression. This may be the consequence of a tight regulation of this
ED
pathway during pregnancy with many forces modulating IDO, including its induction by immune activation, cytokines and oxidative stress, and negative feedback or regulatory effects by CRP,
PT
IgM responses to OSEs and MDA, and nitrosylation.
CE
Delivery-related changes in pro-inflammatory cytokines, including increased signs of IL1 signaling and IL-6 trans-signaling, are associated with puerperal blues but probably less or not
AC
at all with prenatal depression. The acute depletion of plasma levels of LIF-R after delivery may exaggerate the inflammatory response in the early puerperium. There is some evidence that delivery-related changes in plasma tryptophan (decreasing) and kynurenine (increasing), which are both associated with immune activation in the early puerperium, are associated with puerperal blues. Some changes in anti-inflammatory biomarkers at the end of term predict later
ACCEPTED MANUSCRIPT 33
postpartum
depression,
including
lowered
CC16,
an
endogenous
cytokine,
and
ω3
polyunsaturated fatty acids (PUFAs), which regulate cytokine and prostaglandin production. Overall, some biomarkers of mood disorders also play also a role in prenatal depression and, consequently, these pathways may in part explain the links between lifetime histories of
oxidation
and
NOx production seem pregnancy-specific changes,
IP
protein
T
mood disorders and perinatal depression (including increased CRP and lowered zinc). Increased which when
CR
exaggerated are linked to the onset of prenatal depressive symptoms. No current data indicate which pathways underpin the link between a lifetime history of PMS and perinatal depression.
US
Postpartum depression may be the outcome of many different pathways related to lifetime mood
AN
disorders, PMS and postpartum depression, pregnancy-specific changes in IO&NS pathways, including endogenous anti-inflammatory compounds (CC16 and ω3 PUFAs) and lowered levels
M
of some antioxidants (zinc, TRAP), lowered IgM responses to MDA and other pathways that
ED
underpin the pathophysiology of prenatal depression.
PT
Authorships.
CE
CR and MM designed the study. CR conducted all data base searches. All authors contributed
AC
equally to the writing up of the paper. All authors agreed upon the final version of the paper.
Acknowledgements
This research is funded by Chulalongkorn University; Government Budget. MB is supported by a NHMRC Senior Principal Research Fellowship 1059660.
Conflict of interest
ACCEPTED MANUSCRIPT 34
The authors have no conflict of interest with any commercial or other association in connection with the submitted article.
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Figure 1. Association between prenatal and postpartum depression and how both disorders are associated with mood disorders (MOOD) and premenstrual syndrome (PMS).
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Figure 2. Biomarker findings and pathways in perinatal depression and puerperal blues. LPS = lipopolysaccharide, MDA = malondialdehyde, O&NS = oxidative / nitrosative stress, ω3 PUFA = ω3 polyunsaturated fatty acids, CC16 = Clara cell protein, CRP = C-reactive
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protein, LIF-R = leukemia inhibitory factor receptor.
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Table 1. Pregnancy-specific changes in 6 neuro-immune, neuro-oxidative and neuro-nitrosative pathways and their respective biomarkers, which may be involved in prenatal and postnatal depression
Pathways
Relevant biomarkers as
Pregnancy-specific changes
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assessed in
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perinatal depression
Pregnancy: new set point between inflammatory
Haptoglobin,
and anti-inflammatory mechanisms
zinc
Early puerperium: a more pro-inflammatory state
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C-reactive protein,
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1. Neuro-immune
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research
with decreased anti-inflammatory potential
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Chemokines
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Cytokines
CC16 (uteroglobulin)
Tryptophan, TRYCATs
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2. Tryptophan
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LIF-receptor
IgA and IgM responses
Early puerperium further increase in immune-
directed to the TRYCAT
stimulated TRYCAT pathway activity
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catabolite
Pregnancy: TRYCAT pathway activity is enhanced
pathway
3. Neuro-oxidative
AOPP Zinc, TRAP, SH-groups
Pregnancy: activated neuro-oxidative pathways with elevated protein oxidation at the expense of lowered peroxide levels, and lowered antioxidant
Omega-3 polyunsatutared
levels, including zinc and omega-3 polyunsaturated
fatty acids
fatty acids
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4. Neuro-nitrosative
NOx production
Pregnancy: increased NO production, but no changes in nitration or nitrosylation of proteins
5. Gut-immune-
IgA/IgM responses to
Pregnancy: lowered indices of bacterial
brain
antigens/LPS of Gram-
translocation and thus increased protection against
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estrogen levels
Microbiome
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negative commensal bacteria leaky gut, probably by increased progesterone and
IgM responses to MDA and
Pregnancy: lowered IgM responses to MDA,
autoimmune
other oxidative specific
reflecting attenuated regulatory responses thereby
epitopes
contributing to activated neuro-oxidative and
IgM responses to MDA and NO may negatively
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LIF: leukemia inhibitory factor
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adducts
TRYCATs: tryptophan catabolites
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AOPP: advanced oxidation protein products
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TRAP: total radical trapping antioxidant potential NOx: nitric oxide metabolites MDA: malondiadehyde
neuro-nitrosative pathways
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IgM responses to NO-
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6. Natural
regulate depressive symptoms
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Biomarkers
Major depression
Prenatal depression
Postpartum
↑
↓-
-
↓
Neurotrophic cytokines
-
CC16
↓
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depression
CRP
↑
Zinc
↓
ω3 PUFA Tryptophan
Pro-inflammatory
Anti-inflammatory cytokines
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cytokines
-
↓
↓
↑
↑
↓
↓
↓
?
↓
↓
?
↓ in postpartum blues
Kynurenine
↓
-
↓
Anthranilic acid
↓
↓
?
IDO activity
↑ physiosomatic
↑Physiosomatic
↑ in postpartum blues
symptoms
symptoms
Lipid peroxidation
↑
↓
?
TRAP
↓
↓
?
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availability
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-
?
Protein oxidation
↑
↑
↑
IgM directed to MDA
↑
↓
-
NO metabolites
↑
↑
-
IgM directed to NO-
↑
↓
-
↑
↓ in pregnancy
Translocation Gram-
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adducts
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bacteria
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CC16: uteroglobulin CRP: C-reactive protein
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IDO: indoleamine-2,3-dioxygenase
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TRAP: total radical trapping plasma antioxidant parameter
MDA: malondialdehyde
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NO: nitric oxide or nitroso
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PON: paraoxonase
Shown in bold: pathways or compounds that are shared among non-pregnancy related major depression
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Highlights
Postpartum depression is predicted by end of term prenatal depression (pnd)
Activated neuro-immune pathways are associated with pnd
Neuro-oxidative pathways and lowered antioxidant levels are associated with pnd
Neuro-nitrosative stress pathways with increased nitric oxide are linked to pnd
Protein oxidation and lowered zinc are the most important biomarkers of pnd.
Lowered natural IgM-mediated autoimmune responses in pregnancy are involved in pnd
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