Depression and anxiety: Role of mitochondria

ARTICLE IN PRESS Current Anaesthesia & Critical Care (2007) 18, 34–41

www.elsevier.com/locate/cacc

FOCUS ON: NEUROSCIENCE

Depression and anxiety: Role of mitochondria Stephanie Burroughsa,b,, Denise Frenchb a

Centre for Integrative Neuroscience, School of Biological and Biomedical Sciences, Durham University, UK Sunderland Pharmacy School, Sunderland University, Sunderland, Tyne and Wear, UK

b

KEYWORD Mood disorders; BDNF; Glutamate; Mitochondria; Ant-depressants

Summary Depressive and anxiety disorders appear to share an underlying element of distress, forming a general class of mood disorders. The diagnosis of chronic stress-related disorders can be difficult because of non-specific symptoms being masked by other co-morbid states that may also be inadequately described by the patient. Co-morbidity with psychiatric disorders is common, especially in major depressive disorder. It is important to differentiate chronic and acute stress-related disorders, triggered by life events or stressors. Dysfunction in monoamine neurotransmitter systems have for the last 40 years remained the central model considered to play an important role in mediating the physiological and cognitive aspects of depression. The pharmacological action of antidepressants occurs within minutes to hours after administration, but the clinical effect and alleviation of symptoms can take 10–14 days following chronic administration. The discrepancy between pharmacological action and clinical relief of symptoms implies that monoamine depletion alone forming the underlying pathogenesis of depression may be oversimplified. Several neurotransmitters and neuropeptides play a role in the complex neuroanatomical pathways in anxiety. Complex intracellular cascades upregulated in stress-related disorders appear to be intimately associated with the metabolic integrity and capacity of mitochondria to maintain energetic parameters and ultimately cellular stability. Future therapeutic intervention may lie in understanding the interrelationship between hormonal, metabolic and molecular intracellular signaling pathways involved in these conditions. Thus, targeting mitochondrial function may represent a novel avenue for the development of therapies for the treatment of stress-related disorders. & 2007 Elsevier Ltd. All rights reserved.

Introduction

Corresponding author. Centre for Integrative Neuroscience, School of Biological and Biomedical Sciences, Durham University, UK. E-mail address: [email protected] (S. Burroughs).

Mood disorders are a group of mental conditions that rank amongst the top ten causes of disability worldwide.1 The relationship between depression and anxiety stems from the high rates of comorbidity between the two conditions.2 While

0953-7112/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cacc.2007.01.007

ARTICLE IN PRESS Depression and anxiety: role of mitochondria prevalence varies depending on the specific disorder, epidemiological studies generally report that lifetime diagnoses of depression and anxiety cooccur approximately 40–75% of the time.2 In recent years, there have been several theories to explain the relationship between the two, caused by symptoms that are common to both depressive and anxiety disorders.2 Depression and anxiety appear to share an underlying element of distress, forming a general class of mood disorders.2 Individuals with both conditions have a poorer prognosis than those suffering from depression or anxiety alone.2 Although genetic factors play a major, unquestionable role in the aetiology of these disorders,1 the biochemical abnormalities underlying individual predisposition toward, and the pathophysiology involved in mood disorders remain to be fully elucidated.3 Potent anxiolytic and antidepressant agents, such as monoamine oxidase inhibitors (MAOIs) and neurosteroids, may improve and protect mitochondrial efficiency and function against a variety of insults, suggesting mitochondrial function may be linked to the pathophysiology and treatment of behavioural/mood disorders.3 Furthermore, neuro-imaging studies of depressed individuals show abnormalities in glucose metabolism and cerebral blood flow in various brain regions including the limbic and prefrontal cortex, the hippocampus and amygdala.4 However, mood disorders such as depression and anxiety do appear to be distinguished from each other by particular characteristics.2

Mitochondria Targeting mitochondrial function may represent a novel avenue for the development of therapeutics for the treatment of stress-related disorders.3 Mitochondria are organelles found in the cytoplasm of most eukaryotic cells. They are spherical or elliptical in shape, with general dimensions of 1–2 mm in length by 0.5–1 mm in width.5 Structurally, mitochondria are bound by two membranes that create two distinct compartments separated by an intermembrane space.5 The outer membrane encloses the entire organelle and is permeable to small molecules and ionic species, but recent studies suggest that it might form a more important and potentially regulated barrier via specific transporters.6 The inner membrane forms an invaginated high surface area containing cristae that project into and enclose the matrix.6 The central role of mitochondria in respiring cells of eukaryotic organisms is aerobic catabolism of dietary intermediates, i.e. fatty acids and amino

35 acids, to the three carbon intermediate, pyruvate.6 Pyruvate is transported into the mitochondrial matrix by pyruvate dehydrogenase and subsequently undergoes oxidative decarboxylation to the two carbon intermediate, acetyl CoA.6 Acetyl CoA enters the TCA cycle and combines with oxaloacetate which is further oxidised6 generating carbon dioxide, and reducing NAD+ to NADH and FAD2+ to FADH2.6 Oxidation of these respiratory substrates is coupled to phosphorylation of adenosine diphosphate (ADP) and inorganic phosphate (Pi) via the electron transport chain (ETC).6 Anaerobic glycolysis can provide enough adenosine triphosphate (ATP) for some cells, but energetically active cells such as cardiomyocytes and neurons require a more efficient ATP supply, which can only be provided by mitochondrial oxidative phosphorylation via ETC.7 The cristae of the inner mitochondrial membrane are the site at which the components of the ETC are localised.5,6 The respiratory chain is composed of five multi subunit enzyme complexes: NADH-ubiqui none reductase, (complex I), succinate-ubiquinone reductase, (complex II), ubiquinone-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV) and ATP synthase (complex V). The chain also includes lipid soluble mobile electron carriers: ubiquinone (coenzyme Q) and cytochrome c responsible for shuttling electrons from both complexes I and II to complex III, whilst cytochrome c transports electrons from complexes III to IV.6,8 According to the chemio-osmotic principle,9 a series of successive exergonic (energy releasing) redox reactions transfers electrons through the flavin mono nucleotides (FMN) and iron-sulphur (FeS) centres within the ETC complexes providing enough energy to translocate protons from the matrix to the intermembrane space.8 The transfer of protons across the inner membrane at complexes I, III and IV establishes a trans-membrane electrochemical gradient of 180–220 mV negative to the cytosol.6,8,10,11 The extruded protons re-enter the mitochondria via the Complex V (ATP synthase), coupling their transfer to the synthesis of a high-energy intermediate, ATP.11–13 The final electron acceptor is molecular oxygen, which is reduced through a four electron addition to water.11 Chance and Williams14 developed the polarographic method using an oxygen electrode for measuring respiratory rates in cells and subcellular systems including isolated mitochondria.15 The ratio between the respiratory rate during state 3 (active state of respiration) and the return to state 4 (controlled respiratory rate after all ADP is phosphorylated) is called the respiratory control index (RCI); this gives a ratio which allows one to

ARTICLE IN PRESS 36 ascertain the integrity of coupling of oxidation and reduction within the ETC to phosphorylation of ADP to ATP.16

Depression Depressive disorders are generally characterized by low mood, abnormalities in sleep patterns, emotional and physical withdrawal and are often associated with severe morbidity, increased risk of suicide and in some cases psychotic symptoms.17 There are four sub-classifications within major mood disorders: major depression (unipolar) is the most prevalent, affecting women twice as often as men.17 Other major disorders include bipolar depression with recurrent episodes of mania followed by depression, whilst the chronic conditions dysthymia and cyclothymia are considered milder forms of depression.1,17 The exact cause of depressive disorders remains poorly understood but biological, psychological and socio-cultural factors that appear to precipitate these conditions are becoming more clearly elucidated.17 Several neurotransmitter systems, serotonin, noradrenaline, dopamine, glutamate and g-amino-butyric acid have all been implicated in the aetiology of depression and mania.17,18 The monoamine hypothesis of depressive disorders has, for the last 40 years, remained the central model based upon the discovery that the tranquilizing agent reserpine depletes monoamines, producing symptoms of depression.17 Traditional antidepressants such as monoamine oxidase (MAO) inhibitors, tricyclic antidepressants (TCAs) and serotonin re-uptake inhibitors (SSRIs) treat depressive conditions by enhancing synaptic concentrations of dopamine, serotonin and noradenaline; thus, increasing availability of neurotransmitter for postsynaptic neurotransmission.1,19 After neurotransmitter release from presynaptic vesicles, the primary mechanism of action underlying the antidepressant activity of SSRIs and TCAs is blockade or inhibition of reuptake transporters in the presynaptic nerve terminals, thereby preventing clearance of noradrenaline, dopamine and serotonin in the synaptic cleft.19 MAO inhibitors of the enzyme MAO prevent degradation and increase reserves of monoamines within nerve terminal.1,17 The pharmacological action of antidepressants occurs within minutes to hours after administration, but the clinical effects and alleviation of symptoms can take 10–14 days following chronic administration.17 The discrepancy between pharmacological action and clinical relief of symptoms implies that monoamine depletion alone as the underlying basis contributing toward pathogenesis of depression may be

S. Burroughs, D. French oversimplified.17 This argument has been illustrated by the introduction of atypical antidepressants like Tianeptine that enhance serotonin uptake and reduce levels of the transmitter in the synaptic cleft for postsynaptic neurotransmission.19 This mode of action deviates from the traditional therapeutic model of SSRIs and TCAs and has begun to cast doubt upon whether enhancing postsynaptic monoamine neurotransmission is the major therapeutic mode of action required to alleviate depression.19 The downstream cascades resulting from cellular events and adaptive brain processes beyond enhancement of monamine neurotransmission may conceal the true biological nature and therapeutic effects of antidepressants.18 Whilst dysfunction in monoamine neurotransmitter systems is considered to play an important role in mediating the physiological and cognitive aspects of depression, it is becoming more apparent that these events are far more likely to represent the downstream product of earlier changes or abnormalities in intracellular signalling pathways that now form the focus of intense research.18

Anxiety Anxiety disorders are characterized as five major distinct conditions: generalised anxiety disorder (GAD), obsessive–compulsive disorder (OCD), panic disorder, phobias, including social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD).20 The most common anxiety disorders are SAD (lifetime prevalence SAD (12.1%), PTSD (6.8%), and GAD (5.7%).20 The diagnosis of chronic anxiety disorders can be difficult, due to the presence of non-specific or vague symptoms that may be masked by other comorbid states that may also be inadequately described or expressed by the patient.20 Physical symptoms, such as chest pain, fatigue, headache, insomnia, shortness of breath, dizziness, nausea, palpitations, and numbness, are often non-specific and may mimic the patient’s existing co-morbid condition, further complicating the differential diagnosis of an anxiety disorder.20 Co-morbidity with psychiatric disorders is common, especially major depressive disorder, but others include multiple anxiety disorders (panic disorder, SAD, PTSD, GAD), and dementia.20 It is important to differentiate chronic anxiety disorders from acute anxiety, triggered by life events or stressors or anxiety due to other psychiatric conditions.20 Anxiety, although not identical to fear, is closely linked to fear response.21 Fear-learning, such as fear-conditioning in behavioural models, recruits a

ARTICLE IN PRESS Depression and anxiety: role of mitochondria neuroanatomical network centred around the key structure coordinating response to fear, the amygdala.21 Glutamate and gamma-aminobutyric acid (GABA) are abundant in the amygdala and other limbic and cortical structures.22 GABA is the major inhibitory neurotransmitter in the central nervous system.21,22 In the treatment and neurobiology of anxiety disorders, some interest has been focused on possible abnormalities in GABA neurotransmission and the benzodiazepine site of the GABAA receptor.22 Imaging studies in anxiety disorders focusing on the GABA system have shown alterations in benzodiazepine site binding in several brain regions in.21 The anxiolytic benzodiazepines increase GABA neurotransmission to induce a decrease in excitatory output of the amygdala.22 Although benzodiazepines have been the major pharmacological treatment of anxiety disorders for many years, newer agents that modulate GABA neurotransmission, either by inhibiting its reuptake, inhibiting catabolic breakdown, or regulating its transporter, are now available.21 Benzodiazepines are not ideal due to their well known cognitive and sedative properties, as well as their tendency to induce tolerance and dependence in long-term use. Several other neurotransmitters and neuropeptides play a role in the complex neuroanatomical pathways in anxiety and fear conditioning.22 Studies have demonstrated the therapeutic efficacy of drugs selectively targeting 5-HT receptors in anxiety disorders.22 Consequently, 5-HT is hypothesised to modulate defensive mechanisms, therefore having an indirect influence on anxiety.22 Corticotrophin release hormone (CRH) is hypothesised to facilitate anxiety reactions by activation of the central amygdala nucleus.22 The noradrenergic and dopaminergic systems are believed to increase arousal in response to threat via an indirect pathway through the amygdala.22 There are two types of treatment for anxiety disorders, psychotherapy and pharmacotherapy.20 Psychotherapy has been effective for specific phobias, whereas pharmacotherapy alone or in combination with psychotherapy has been considered the standard treatment for most anxiety disorders.20 Anxiolytic agents, of which benzodiazepines and buspirone are the principal members may be used for acute anxiety relief for a limited period, but, in general, patients should begin treatment for chronic anxiety disorder with an antidepressant (either a selective serotonin reuptake inhibitor (SSRI) or a mixed-mechanism antidepressant).20

37

Molecular aspects of anxiety and depression Hypothalamic–pituitary–adrenal axis (HPA) axis One of the major defining neurobiological features of stress disorders is hyperactivity of the hypothalamic–pituitary–adrenal axis (HPA) with subsequent elevated glucocorticoid levels.23 Glucocorticoids, primarily cortisol (in humans and most mammals) or corticosterone (in rats, mice and lower vertebrates), are steroid hormones released by the adrenal cortex in response to stress and are the final products of the HPA axis via a complex interaction of hormone signals.24–27 Upon exposure to stress, corticotrophin releasing hormone (CRH) is upregulated in neurons of the paraventricular nucleus (PVN) in the hypothalamus.22,28 The PVN is responsible for initiating HPA axis activity during a stress response.29 CRH is then released from the terminals of paraventricular neurons and transported to the anterior pituitary to stimulate the synthesis of adrenocorticotrophic hormone (ACTH), which binds to widely distributed CRH type 1 receptors and appears to transduce the effects of CRH during stress.23,30 Secretion of ACTH into the systemic circulation stimulates receptors in the adrenal cortex, resulting in the release of glucocorticoids, namely cortisol.19,30 Glucocorticoids bind to both mineralocorticoid (MR) and glucocorticoid receptors (GR), with a 10-fold lower affinity to the latter.24–26 The difference in affinity is thought to manipulate the different properties of the MR or GR, where MRs are thought to involve evaluation of current situations and response selection, whilst GRs are involved in the consolidation of recently acquired information.24 At low glucocorticoid concentrations (e.g. during everyday activities), MR is activated whilst at high glucocorticoid concentrations (e.g. during stress) GR is activated, exhibiting very different physiological effects.31 In a shortterm crisis e.g. during stress, cortisol release provides energy by promoting glyconeogenesis, increasing blood glucose and glycogen formation in the liver19 at the expense of long-term physiological processes that are not crucial for immediate survival.31 Persistent or repetitive stress may cause sensitive stress pathways to become markedly hyperactive, leading to persistent increases in CRH and cortisol secretion.30 This, in turn, could cause alterations in GR and thereby contribute to the pathogenesis of stress disorders.30 There is evidence to suggest that elevated levels of glucocorticoids affect the function of mitochon-

ARTICLE IN PRESS 38 dria.32 Cortisol activates the GR receptor which can associate with several chaperone proteins to form a GR complex.32 The complex then translocates from the cytosol to the nucleus of the cell.32 In the nucleus, GR directly binds to glucocorticoid response element in DNA to regulate transcription, including Bcl-2 associated X protein (BAX), a pro-apoptotic protein belonging to the B-cell lymphoma 2 (BCl-2) family.32 The binding of GR and BAX to mitochondrial membranes can contribute to regulation of the mitochondrial membrane potential (MMP).32 GR- or BAX-induced changes in membrane potential can result in the release of cytochrome c from the intermembrane space of mitochondria to the cytosol, where it activates and promotes caspasedependant cell death i.e. apoptosis.32 The MMP reflects and influences the integrity and performance of the ETC.33 Ultimately, chronically elevated stress induced cortisol levels, may compromise cellular energy capacity and increase vulnerability of neurons to toxic events by lowering levels of glucose available to the TCA cycle and ETC.20

Bcl-2 It has been proposed that rather than killing neurons directly, exposure to high concentrations of corticosteroids typically induces a physiological state that renders neurons more susceptible to subsequent neurological insults. DeVries et al.34 suggest suppression of Bcl-2 expression may be one such mechanism through which stress compromises neuronal survival following stroke. The Bcl-2 family consists of anti-apoptotic members (including Bcl-2 and Bcl-xL) and pro-apoptotic members (such as BAX and BAD3). Studies have shown over-expression of Bcl-2 in mitochondria in cultured cells suppresses apoptosis by inhibiting calcium activation of the permeability transition of mitochondria,35 thus protecting mitochondrial membrane integrity and preventing the release of cytochrome c.3 The release of cytochrome c may initiate apoptosis by inducing the binding of apoptotic protease activating factor 1 (Apaf1) to cytochrome c and deoxyATP to form an apoptosome thus initiating the caspase cascade pathway that subsequently leads to apoptosis.36 Therefore, stress-induced downregulation of Bcl-2 may render the ETC more susceptible to damage. Recent studies suggest that Bcl-2 may have a more general role in regulating mitochondrial metabolism and function, where its protective effect may not be limited to an anti-apoptotic role.3 An investigation by Einat et al.3 exploring the behavioural outcome of mice with a targeted mutation of the Bcl-2 gene (heterozygote mice) in

S. Burroughs, D. French behavioural models of psychiatric disorders, demonstrated an increase in anxiety-like behaviours in mice with reduced mitochondrial Bcl-2 levels. This suggests that mitochondrial function, modulated by Bcl-2, may be related to the regulation of stress-induced behaviours and may be critical in the aetiology of stress disorders.3

Brain derived neurotrophic factor (BDNF) Studies have shown that downregulation of brain derived neurotrophic factor (BDNF) occurs during stress, and antidepressants may promote BDNF expression.37 BDNF binds to a high-affinity cell surface tyrosine kinase receptor B (trkB38–41 mediating postsynaptic rises in cAMP concentrations that facilitate translocation of TrkB into the postsynaptic neuron.41 This subsequently triggers autophosphorylation of tyrosine residues in its intracellular domain42 leading to activation of one or more of the three major signalling pathways involving mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase, (PI3K)-Akt and phospholipase Cg (PLC-g) pathways.18,41 This sequence of events results in the activation, through a series of proteins, of the extracellular signal regulated kinase 1 and 2 (ERK1/2) MAPK cascade.38 Evidence suggests that activation of the MAPK may inhibit apoptosis by inducing the enzyme S-6-kinase (Rsk), which phosphorylates the proapoptotic protein BAD, and increases the expression of Bcl-2, possibly via the cAMP response element binding protein CREB.18,38 Activation of Rsk can mediate the actions of the MAPK cascade and neurotrophic factors, as well as phosphorylation of CREB, leading to an induction of Bcl-2 gene expression.38 BDNF has been shown to induce a concentration dependant increase in RCI of rat brain mitochondria via an MAPK pathway, the effect being highly specific to for oxidation of complex I but not complex II.40

Calcium excitotoxicity It is now understood that specific regions within the brain such as the hippocampus, prefrontal cortex and amygdala are capable of adaptive or remodelling responses to sensory, cognitive, emotional, social and endocrine input.4 Limbic regions of the adult human brain are considered to be plastic in nature, especially the hippocampus where neural progenitor cells continue to undergo division, adding new neurons to the adult brain.43 Stressinduced impairment of multiple neuronal pathways suppress neurogenesis and cause atrophy of these brain structures which are involved in learning and

ARTICLE IN PRESS Depression and anxiety: role of mitochondria memory.4,44 Cellular signalling mechanisms promote strengthening of synaptic connections leading to long-term potentiation (LTP), thus altering and adapting brain structures which are thought to be fundamental to neuronal plasticity and to how the brain acquires, processes and retains information i.e. learning and memory.44 Stimulation of Nmethyl-D-aspartate (NMDA) receptors in neurons not only underlies activity-dependent changes in LTP, but is linked to pathological changes leading to neurotoxic damage.45 Recent developments in the neurobiology of stress disorders have highlighted the neurotransmitter glutamate (L-glutamic acid) as an important element in behaviours defining stress disorders.22 Glutamate is the major excitatory neurotransmitter in the central nervous system in mammals. The spectrum of excitation by glutamate ranges from normal to excess neurotransmission, causing pathological symptoms such as mania or panic, to excitotoxicity resulting in minor damage to dendrites.22 There are three families of ionotropic glutamate receptors (NMDA), 2a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) and kainate receptors22,46,47 which are mainly postsynaptic and regulate fast excitations and synaptic plasticity associated with the opening of cation-permeable ligand-gated ion channels.47,48 AMPA and kainate receptors (non-NMDA receptors) are associated with voltage-independent channels that gate a depolarising current mainly carried by Na+ ions,46 which in turn promote the activation of voltagedependent NMDA receptors.22,46 Glutamate is released from vesicles in presynaptic terminals by a calcium-dependent mechanism that involves voltage-dependent calcium channels.47 Glutamate and glycine (D-serine) act on the NMDA recognition site and glycine co-agonist site, respectively, which are situated on different subunits of the multisubunit NMDA receptor complex.49 At normal resting membrane potentials, NMDA receptors are inactive due to a voltagedependent block of the receptor channel by Mg2+ ions, which prevents current flow.46 Depolarisation of the postsynaptic membrane by activation of other receptor subtypes, such as AMPA or kainate receptors, removes the Mg2+ block, therefore activation of the NMDA receptor occurs with subsequent influx of Ca2+ and other ions through the NMDA receptor channel, which has a role in synaptic plasticity.22,46 Mitochondria are also involved in the regulation of intracellular calcium (Ca2+), and are critical mediators of apoptosis. During stress, glutamatergic transmission is increased,21 therefore

39 glutamate overactivates its receptors leading to a sustained influx of calcium.50 These events can be followed by excessive mitochondrial calcium sequestration,51 calcium-induced mitochondrial swelling, depolarisation, uncoupling of oxidative phosphorylation and oxidative stress.18,52,53 Under pathological conditions e.g. excessive glutamate exposure during stress, mitochondria of CNS neurons accumulate large amounts of calcium54 in order to compensate or buffer high levels of free cytosolic calcium. Accumulation of mitochondrial calcium is thought to generate reactive oxygen species (ROS) via the ETC.6 In most cell types, mitochondria appear to represent one of the major sources of free radicals or ROS.6 A consequence of the action of oxidative phosphorylation is the generation of unpaired electrons that interact with O2 resulting in the generation of superoxide ions, highly reactive free radical species.6 These are readily converted to other radical species, such as hydroxyl ions (OH ) and hydrogen peroxide (H2O2),6 which are thought to damage the ETC of the mitochondria. ROS may cause lipid peroxidation and damage to cell membranes and DNA, including mitochondrial DNA (mtDNA), which has no associated histones and is therefore less protected from radical damage than nuclear DNA.6 Elevated levels of glutamate induced by stress may also induce ‘‘oxidative’’ glutamate toxicity via the depletion of glutathione (GSH).6 This is due to competition between glutamate and cysteine for the cysteine transporter, preventing the supply of cysteine required for resynthesis of GSH.6 GSH functions as a major anti-oxidant responsible for removing ROS, and oxidative toxicity, following the depletion of GSH involves an increase in net mitochondrial ROS production.6

Summary The link between complex intracellular cascades upregulated in stress-related disorders such as anxiety and depression are intimately associated with the metabolic integrity and capacity of mitochondria to maintain energetic parameters and ultimately cellular stability. Recent data have suggested that anxiety appears to have a timedependent impairment of brain mitochondrial function.55 The immediate effects may be the result of fast acting glutamate-induced calcium excitotoxicity, whereby the generation of ROS may disrupt the integrity of the complexes within the ETC. Furthermore, delayed effects may upregulate pro-apoptotic proteins by GR activation and/or the reduction of BDNF stimulation during anxiety thus

ARTICLE IN PRESS 40 inhibiting the MAPK pathway and consequently the protective role of Bcl-2. Recent developments elucidating the complex nature of anxious and depressive states provide indications that effective future therapeutic intervention may lie in understanding the interrelationship between hormonal, metabolic and molecular intracellular signalling pathways involved in these conditions.56

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