N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update

European Journal of Pharmacology 785 (2016) 187–206

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update Marc-Olivier Trépanier, Kathryn E. Hopperton, Sarah K. Orr, Richard P. Bazinet n Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 3E2

art ic l e i nf o

a b s t r a c t

Article history: Received 4 February 2015 Received in revised form 13 April 2015 Accepted 21 May 2015 Available online 30 May 2015

Neuroinflammation is a characteristic of a multitude of neurological and psychiatric disorders. Modulating inflammatory pathways offers a potential therapeutic target in these disorders. Omega-3 polyunsaturated fatty acids have anti-inflammatory and pro-resolving properties in the periphery, however, their effect on neuroinflammation is less studied. This review summarizes 61 animal studies that tested the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory outcomes in vivo in various models including stroke, spinal cord injury, aging, Alzheimer’s disease, Parkinson’s disease, lipopolysaccharide and IL-1β injections, diabetes, neuropathic pain, traumatic brain injury, depression, surgically induced cognitive decline, whole body irradiation, amyotrophic lateral sclerosis, N-methyl-D-aspartateinduced excitotoxicity and lupus. The evidence presented in this review suggests anti-neuroinflammatory properties of omega-3 polyunsaturated fatty acids, however, it is not clear by which mechanism omega-3 polyunsaturated fatty acids exert their effect. Future research should aim to isolate the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory signaling in vivo and elucidate the mechanisms underlying these effects. & 2016 Published by Elsevier B.V.

Keywords: Neuroinflammation Omega-3 polyunsaturated fatty acids Brain Cytokines Microglia Docosahexaenoic acid

1. Introduction Inflammation is a characteristic of many neurological and psychiatric illnesses, including Alzheimer’s disease, multiple sclerosis, depression, schizophrenia and Parkinson’s disease (Glass et al., 2010; Najjar et al., 2013). While some inflammation is integral for pathogen and debris clearance, as well as wound healing, excessive, dysregulated inflammation can exacerbate tissue injury (Carson et al., 2006b; Chhor et al., 2013; Glass et al., 2010). Indeed, inflammation has been suggested as a mechanism by which Alzheimer’s and Parkinson’s disease pathologies potentiate neuronal death (Glass et al., 2010; Heneka et al., 2015). The brain is an immunologically unique environment, and as such, knowledge about inflammation and its resolution in the periphery may not apply directly to the brain (Carson et al., 2006a). The brain is separated from the periphery by the blood– brain-barrier (BBB), and houses its own population of immune effector cells: astrocytes and microglia. Microglia are the macrophages of the brain, and under normal conditions, exist in the M0 resting phenotype, surveying the neurological environment for insult or injury (Prinz and Priller, 2014). Microglia can be activated n Correspondence to: University of Toronto, Department of Nutritional Sciences Faculty of Medicine, FitzGerald Building, 150 College St., Room 306, Toronto, ON Canada M5S 3E2. Fax.: þ 1 416 978 5882 E-mail address: [email protected] (R.P. Bazinet).

http://dx.doi.org/10.1016/j.ejphar.2015.05.045 0014-2999/& 2016 Published by Elsevier B.V.

from their resting M0 state to a M1 pro-inflammatory state by cytokines such as tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ), produced either by the microglia themselves or by astrocytes, the major glial cells of the brain, in response to insult recognition (Cherry et al., 2014; Hanisch and Kettenmann, 2007). Once activated, M1 microglia are characterized by production of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-1β, IL-12, IFN-γ, IL-1α and chemokine (c-x-c motif) ligand (CXCL) 11, increased activity of cyclooxygenase (COX)-2 and production of pro-inflammatory lipid mediators such as prostaglandin (PG) E2, and an increased production of reactive oxygen and nitrogen species via activity of inducible nitric oxide synthase and NADPH oxidase (Chhor et al., 2013; Prinz and Priller, 2014). Pro-inflammatory cytokines also activate astrocytes, which contribute to cytokine, reactive oxygen species and nitric oxide production (Saijo et al., 2009). Exaggerated innate immune responses or the failure to clear insults can lead to excessive production of cytokines and reactive oxygen species by astrocytes and microglia, which trigger neuronal death by apoptosis or necrosis, feeding forward to further activate microglia by releasing ATP and calcium into the extracellular space (Glass et al., 2010; Prinz and Priller, 2014; Saijo et al., 2009). Upon neutralization of the initial insult and/or in response to cytokine IL-4 and chemokine (c-c motif) ligand (CCL) 2, M1 microglia switch to a M2 anti-inflammatory phenotype, promoting phagocytosis, wound healing and a return to homeostasis (Cherry et al., 2014; Hanisch and

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Kettenmann, 2007). Despite the presence of the BBB, neuroinflammation can also be influenced by peripheral factors. Pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6 and TNF-α have all been shown to cross the BBB, seemingly regulated by specific transporters (Banks, 2015). Permeability of the BBB to these factors increases under some neurological conditions, allowing peripheral macrophages, neutrophils and T cells to enter the brain (Banks, 2015; Carson et al., 2006a; Prinz and Priller, 2014; Wang et al., 2014e). Clearly, neuroinflammation is a distinct and complex process that results from interplay between a variety of cell types and mediators. As neuroinflammation has been implicated in the pathogenesis of various neurological disorders, there has been interest in the role of anti-inflammatory drugs for their prevention and treatment. In human observational studies, the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) is associated with a decreased risk of Alzheimer’s disease, with longer-term users exhibiting the greatest risk reduction (Wang et al., 2014b). Ibuprofen use is associated with a decreased risk of Parkinson’s disease, although aspirin and other NSAID do not seem to exhibit the same protective effects (Rees et al., 2011). Randomized clinical trials, on the other hand, generally do not support the positive effects of NSAID in these neurological diseases. For instance, the only randomized control trial testing NSAID in primary prevention of Alzheimer’s disease found that neither celecoxib nor naproxen reduced the risk of Alzheimer’s Disease onset, although this trial was stopped with an average of 15 months follow-up, well short of the target 7 years, due to concerns over increased cardiovascular risk with celecoxib treatment (ADAPT Research Group, 2013). Randomized clinical trials of anti-inflammatory drugs in patients with Alzheimer’s disease or mild cognitive impairment have also generally failed to show any benefits (Jaturapatporn et al., 2012), and in some cases, have reported serious adverse events, with one trial finding that rofecoxib (selective COX-2 inhibitor) increased the risk of patients with mild cognitive impairment progressing to Alzheimer’s disease (Thal et al., 2005). The evidence suggests that although neuroinflammation is implicated in neurological disease, blocking inflammation may not be therapeutic. In animal models, blocking inflammation via reduced activity of microglia exacerbates acute neural injury to hypoxia (Lalancette-Hebert et al., 2007), and acute administration of exogenous activated microglia immediately following ischemiareperfusion improves recovery (Imai et al., 2007). In mice, deletion or disruption of the COX-2 gene exacerbates the neuroinflammatory response to lipopolysaccharide (LPS) and fails to provide any benefit in models of Parkinson’s disease and traumatic brain injury, while pharmaceutical COX-2 inhibitors have mixed effects in neuroinflammatory disease models (Choi et al., 2009). In a transgenic model of Alzheimer’s disease, a mildly pyrogenic agonist of toll-like receptor (TLR) 4, a receptor on the surface of microglia, improved amyloid-β (Aβ) clearance and cognitive measures, while the much more potent TLR4 agonist, LPS, did not (Michaud et al., 2013). Thus, interventions that can modulate, as opposed to block, neuroinflammation may be a useful therapeutic approach. The resolution of inflammation was historically thought to be a passive process resulting from the dissipation of pro-inflammatory mediators (Serhan et al., 2008). A novel class of molecules produced from the omega (n)-3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid and eicosapentaenoic acid (DHA and EPA, respectively), collectively referred to as specialized pro-resolving mediators (SPM), stimulate resolution, actively returning tissue to homeostasis following inflammation (Serhan, 2014; Serhan et al., 2008). SPM, comprising of the resolvin (Rv), protectin and maresin families, offer a potential mechanism for the protective effects of n-3 PUFA on neurological diseases that have been observed in

animal models and human observational studies (Hashimoto et al., 2014; Hooijmans et al., 2012; Najjar et al., 2013). The two main PUFA species in the brain are DHA and arachidonic acid (ARA), an n-6 PUFA. DHA and ARA can be consumed preformed from the diet, or synthesized from dietary precursors, α-linolenic (ALA, a n-3 PUFA) or linoleic (a n-6 PUFA) fatty acids, primarily in the liver. While the brain expresses enzymes that can synthesize DHA and ARA from their dietary precursors, these synthesis rates appear to be much lower than the rate of brain PUFA uptake from the plasma, suggesting the brain is largely dependent on preformed DHA and ARA synthesized in the liver, or supplied directly from the diet (Bazinet and Laye, 2014; DeMar et al., 2006; Igarashi et al., 2007). Brain lipid metabolism is a complex and evolving field (for review see (Liu et al., 2014)). Briefly, upon entry into the brain, DHA and ARA are mostly esterified to phospholipids at the stereospecifically numbered-2 position. DHA and ARA are both released from phospholipids by phospholipase (PL) A2, with ARA preferentially cleaved by calciumdependent cytosolic PLA2, and DHA by calcium-independent PLA2 (Green et al., 2008). While over 90% of DHA and ARA released from the phospholipid membrane are rapidly re-esterified to phospholipids, a process known as the Lands cycle, a proportion of these unesterified fatty acids can be used as substrates for the synthesis of pro-inflammatory and pro-resolving mediators (Bazinet and Laye, 2014). ARA and DHA are acted upon by COX and lipoxygenase enzymes, with ARA giving rise to pro-inflammatory mediators such as PG (notably PGE2) and leukotrienes and DHA to SPM (Serhan, 2014). It is generally appreciated that n-3 PUFA have anti-inflammatory properties in the periphery (Calder, 2006; Yates et al., 2014). The mechanism by which n-3 PUFA are anti-inflammatory is yet to be determined. One suggested mechanism proposes that by increasing the availability of n-3 PUFA SPM precursors results in increased SPM production. The potent actions of SPM on peripheral immune cells and inflammation are much better studied (Serhan, 2014; Serhan and Chiang, 2013). It has recently been shown that supplementation with fish oil for as little as 5 days produces significant increases in plasma levels of SPM and their precursors, suggesting that diet modifies the body’s inflammatory environment (Barden et al., 2014), although it is important to note that there is variation between studies in the detection of SPM and their precursors at baseline and following n-3 PUFA supplementation (Colas et al., 2014; Dawczynski et al., 2013; Wang et al., 2014d). While studies of SPM in the brain are limited, it is known from postmortem brain samples that patients with Alzheimer’s disease have lower hippocampal levels of SPM protectin D1 (PD1/NPD1) (Lukiw et al., 2005), and lipoxin A4 and RvD1 levels in the cerebrospinal fluid are positively correlated to Mini-Mental State Examination scores (Wang et al., 2014c), which supports a protective role for these mediators in human neurological disease. In general, in vitro evidence points to immunomodulatory effects of DHA and EPA in immortalized microglia and astrocyte cultures, with lower levels of inflammatory markers in response to stimulation with IFN-γ, LPS or Aβ (Hjorth and Freund-Levi, 2012; Orr et al., 2013b). EPA and DHA lower markers of M1 microglia activation and improve phagocytosis of Aβ in microglia cultures, while DHA also increases M2 microglia markers, pointing to a proresolving effect (Hjorth et al., 2013). Cultures of human glial cells produce various DHA-derived SPM in response to stimulation suggesting that SPM may play a role in the brain (Hong et al., 2003). NPD1 decreases Aβ-induced apoptosis in human neuronal cell cultures (Lukiw et al., 2005). In a co-culture of human neuronal and glial cells, NPD1 decreases inflammatory markers COX-2 and TNF-α, increases peroxisome proliferator activated receptor (PPAR) γ, and protects neurons from Aβ-induced cell death (Zhao et al., 2011). Together, these results support a role for n-3 PUFA and

Table 1 Summary of studies investigating the effects of n-3 PUFA in ischemia and ischemia/reperfusion models. Authors (year)

Injury Model

Species

PUFA Treatment(s)

Comparison Treatment

Treatment Duration/ Time point

Brain n-3 PUFA

Non-Inflammatory Outcome

Inflammatory Outcome

Black et al. (1984)

Ischemia/ reperfusion

Mongolian Gerbils

a) 0.833 mg EPA i.v., b) 0.167 mg EPA i.v

0.167 mg LA i.v

135 min infusion 5 min prior ischemia

Not reported

a ↑cerebral blow flow a,b2brain edema

a,b

Marcheselli et al. (2003)

Ischemia/ reperfusion

C57BL/6 mice

a) 0.4–120 μg 10,17 S-dihydroxyDHA i.c.v., b) 2–200 μg DHA i.c.v

Vehicle i.c.v

3 or 48 h continuous infusion post-injury

Not reported

b

a,b ↓CX and HIP leukocyte/neutrophil accumulation COX-2 mRNA

Yang et al. (2007)

Ischemia/ reperfusion

Sprague Dawley rats

Saline i.p. Per kg body weight i.p.: a) 250 nmol (71 μg) SA, b) 500 nmol (142 μg) SA, c) 250 nmol (76 μg) ARA, d) 500 nmol (152 μg) ARA, e) 250 nmol (82 μg) DHA, f) 500 nmol (164 μg) DHA

60 min postreperfusion

Not reported

d,f

d,f

Pan et al. (2009)

Ischemia/ reperfusion

Sprague Dawley rats

Per kg body weight i.p.: a) 100 nmol (33 μg) DHA, b) 500 nmol (164 μg) DHA

Saline i.p.

1 h (single), 3 d (single), or 6 weeks# (daily) prior to ischemia

Not reported

b

↓infarct size b↓BBB permeability b ↓apoptosis b # ↓oxidative stress b↓lipid peroxidation

b

Belayev et al. (2009)

Ischemia/ reperfusion

Sprague Dawley rats

14 mg/kg DHA i.v

Saline i.v.

60 min postreperfusion

Not reported

↓ infarct size

↑CX GFAP protein

Zhang et al. (2010)

Ischemia (immature brain)

Sprague Dawley rats (pups)

Chowþ EPA þDHA (15 mg/g of diet)

Low n-3 (0.5% total diet weight)

↑CX total From day DHA and 2 of pregEPA nancy to 7 days post surgery (PND 14)

↑ sensorimotor score (FF) ↑l learning and memory (MWM) ↓infarct size

↓CX COX-2, iNOS, TNF-α, IL-1α, IL-1β, IL-6 mRN A↓ CX, ST Iba1 protein

Belayev et al. (2011)

Ischemia/ reperfusion

Sprague Dawley rats

5 mg/kg DHA i.v

Saline i.v

Time postischemia:3 h 4h 5h 6h

a

↑PN NPD1 and 17HDHA

a,b,c ↓infarct size a,b,c↑sensorimotor score (PRT, FPT)

a

LalancetteHébert et al. (2011)

Ischemia/ reperfusion

TLR2-flucGFP transgenic mice (C57BL/6)

DHA supplemented (0.7% n-3 PUFA total diet)

Low n-3 PUFA (0.03% n-3 PUFA)

12 weeks

↑ST DHA

↓infarct size

↓TLR2 promoter induction ↓brain IL-1β, IL-6, COX-2 protein 2brain TNF-α protein

Okabe et al. (2011)

Ischemia/ reperfusion

Mongolian Gerbils

500 mg/kg EPA i.p

Saline i.p

4 weeks prior to surgery

Not reported

↑CA1 neuronal survival ↓oxidative stress ↑Learning and memory (8ARM)

↓HIP Iba1 protein

Bazan et al. (2012)

Ischemia/ reperfusion

Sprague Dawley

333 μg/kg AT-NPD1 i.v

Saline i.v.

60 min postreperfusion

Not reported

↓infarct size ↑sensorimotor score

↑CX GFAP protein ↓CX CD68 protein 2SCX GFAP and CD68 protein

↓infarct size

↑CX leukocyte/neutrophil accumulation

d,f

a,b

↓HIP NF-κB protein

a,b

↑CX COX-2 mRNA

↓CX leukocyte/neutrophil accumulation b↓CX IL-6 protein

↑CX and ST GFAP protein a↓CX and ST CD68 protein

↓HIP

M.-O. Trépanier et al. / European Journal of Pharmacology 785 (2016) 187–206

↑infarct size

2brain PGF2, PGE2, TXB2, 6-ketoPGF1α

189

Authors (year)

Injury Model

190

Table 1 (continued ) Species

PUFA Treatment(s)

Comparison Treatment

Treatment Duration/ Time point

Brain n-3 PUFA

rats

Non-Inflammatory Outcome

Inflammatory Outcome

(PRT, FPT) 1 h postreperfusion

Not reported

↓ infarct size ↑sensorimotor score (PRT, FPT) ↓pAKT

↑CX GFAP protein ↓CX CD68 protein

Saline i.v. or Per kg body weight i.v.: a) 5 mg DHA, b) 5 mg DHA þ0.32 g Alb, c) 0.63 g/kg Alb 5 mg DHAþ 0.63 g Alb, d) 5 mg DHAþ 1.25 g Alb

1 h postreperfusion

Not reported

a,b,c,d ↑sensorimotor score (PRT, FPT) a,b,c,d↓infarct size a,b,c,d↑new neurons

a,b,c,d

Sprague Dawley rats

Daily 500 nmol (164 μg)/kg i.p. DHA

Saline i.p.

3 days prior to surgery

Not reported

↑neurological score ↓infarct size ↓apoptotic signals ↓oxidative stress

↓CX CD68, CD45, Ly6g, CD3, CD11bprotein ↓CX MPO activity ↓CX TNF-α, IL-1β, CCR2, IL-6, MCP-1 mRNA

Ischemia/ Reperfusion in aged rats (18 mo)

Sprague Dawley rats

Per kg body weigh i.v.: a) 5 mg DHA, b) 5 mg DHA þ0.63 g Alb

Saline or 0.63 g/kg Alb

1 h postreperfusion

Not reported

a,b ↑sensorimotor score (PRT, FPT) b↓edema b↓infarct size a,b↑new neurons

a,b

Luo et al. (2014)

Ischemia/ reperfusion

Fat-1 mice

Fat-1 mice were placed on 10% corn oil

WT were placed on 10% corn oil

Not reported

↑HIP total DHA and n-3 DPA ↑HIP RvD1 (following ischemia)

↑learning and memory (MWM) ↓apoptosis ↓cell death 2GPCR 120 expression

↓HIP NF-κB, TNF-α, IL-1β, IL-6, MCP-1, GFAP, Iba1 protein

Zendedel et al. (2015)

Ischemia/ reperfusion

Wistar rats

Per kg body weight i.v.: 140 mg DHAþ 220 mg EPA

Saline i.v. or Lipofundin MCT

1 and 12 h postischemia

Not reported

↓hypoxic marker ↑axonic, dendritic marker ↑neurological score ↓infarct size

↓brain IL-1β, TNF-α, Arg1, NLRP3 mRNA 2brain Trem2 mRNA

Ischemia/ Reperfusion

Sprague Dawley rats

5 mg/kg DHA i.v

Eady et al. (2012b)

Ischemia/ Reperfusion

Sprague Dawley rats

Chang et al. (2013)

Ischemia

Eady et al. (2014)

Saline i.v.

↑CX, ST GFAP protein

c,d

↓CX, ST CD68 protein

2CX, b↑ST GFAP protein b↓CX, ST CD68 protein

17-HDHA, 17-hydroxy-DHA (DHA derivative); 8ARM, 8-arm radial maze, Aβ, amyloid-β; Alb, albumin; pAKT, phosphorylated protein kinase B; ARA, arachidonic acid; AT-NPD1, aspirin triggered NPD1; BBB, blood brain barrier; C-C motif chemokine; CD, cluster of differentiation; COX, cyclooxygenase; CX, cortex; DHA, docosahexaenoic acid; DPAn-3, docosapentaenoic acid; EPA, eicosapentaenoic acid; FF, foot fault/grid walking; FPT, forelimb placing test; GFAP, glial fibrillary acidic protein; HIP, hippocampus; Iba, ionized calcium-binding adaptor molecule; IL, interleukin; iNOS, nitric oxide synthase; LA, linoleic acid; Ly6G, lymphocyte antigen 6; MCP, monocyte chemotactic protein; MPO, myeloperoxidase; MWM, Morris water maze; NF-κB, nuclear factor kappa light chain enhancer of activated B cell; NLRP3, NLR family pyrin domain containing 3; NPD, neuroprotectin D; PG, prostaglandin; PN, penumbra; PND, postnatal day; PRT, postural reflex test; PUFA, polyunsaturated fatty acid; SA, stearic acid; ST, striatum; TLR2, toll-like receptor 2; TNF, tumor necrosis factor; TX, thromboxane; WT, wildtype; a,b,c,d,e,f indicates treatment group represented in outcome columns (brain n-3 PUFA, primary outcome, inflammatory outcome)

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Eady et al. (2012a)

Table 2 Summary of studies investigating the effects of n-3 PUFA on spinal cord injury models. Authors (year)

Injury model

Species

PUFA treatment(s)

Comparison Treatment

Treatment duration/time point

Brain n-3 PUFA

Non-Inflammatory outcome

Inflammatory Outcome

Lang-Lazdunski et al. (2003)

Ischemia SCI

Sprague–Dawley rats

250 nmol (70 μg)/kg ALA i.v.

Vehicle i.v.

30 min pre surgery or immediately following surgery

Not reported

↑neurological outcome ↓apoptosis ↑neuronal survival

↓spinal NF-κB protein

King et al. (2006)

Hemisection SCI

Wistar rats

Per kg body weight i.v.: a) 250 nmol (82 μg) DHA, b) 250 nmol (70 μg) ALA, c) 250 nmol (76 μg) ARA

Vehicle i.v. 250 nmol/kg OA i.v.

Acute i.v. 30 min post surgery

Not reported

a,b ↓lesion size c↑lesion size a,b↓apoptosis c ↑apoptosis a,b ↑neuronal survival c↓neuronal survival a,b↑oligodendrocyte c survival ↓oligodena,b drocyte survival ↓RNA oxidation c↑RNA oxidation a,b↑motor recovery c2motor recovery

a,b

Huang et al. (2007)

Compression SCI

Sprague Dawley rats

a) 250 nmol (82 μg)/ kg DHA i.v. þ control diet, b) 250 nmol (82 μg)/kg DHA i.v. þ 400 mg/kg/d DHA/EPA p.o

Saline i.v. þcontrol diet

Acute i.v. 30 min post surgery1 or 6 weeks diet post surgery

Not reported

a,b

↑spinal neuronal survival a,b↑spinal oligodendrocyte survival a,b↓ spinal neuron injury a,b↑motor recovery a,b↓RNA oxidation

a,b

Compression SCI

Sprague Dawley rats

250 nmol (82 μg)/kg DHA i.v.

Saline i.v.

Acute i.v. 30 min post surgery

Not reported

↓spinal lipid peroxidation ↓spinal protein oxidation

↓spinal COX-2 protein

Lim et al. (2010)

Compression SCI

Sprague–Dawley rats

250 nmol (76 μg)/kg EPA i.v.

Saline i.v.

Acute i.v. 30 min post surgery

Not reported

↑spinal neuronal survival ↑spinal oligodendrocyte ↓spinal neuron injury ↑motor recovery

2spinal CD68 protein

Figueroa et al. (2012)

Compression SCI

Sprague Dawley rats

250 nmol (82 μg)/kg DHA i.v.

vehicle i.v.

1 h and 1 week prior to injury

Not reported

↑Motor recovery ↑axonal conductance ↑myelin and axonal integrity ↓cell death

2spinal GFAP, CD68, CD11b protein

Hall et al. (2012)

Compression SCI

Sprague Dawley rats

Per kg body weight i.v.: a) 250 nmol (82 μg) DHA, b) 250 nmol (76 μg) EPA

Vehicle i.v.

Acute i.v. 30 min post surgery

Not reported

a,b

2hepatic neutrophil a↓plasma CRP

a

↓ventral horn JTI protein 24hr post-injury and ventrolateral white matter JTI 4hr post-injury a,b2spinal IL-6, IL-1β, TNF-α, KC/GRO/CINC protein

Lim et al. (2013a)

Compression SCI

Fat-1 mice

Fat-1 on 10% corn oil

a) WT littermate on 10% corn oilb) WT littermate on n-3 PUFA adequate diet

12 weeks

↑spinal PL DHA

↑cell survival↑motor recovery

↓spinal Iba1 protein ↓spinal IL6 protein (vs. a only) 2spinal IL-1β protein

c

2spinal CD68 protein ↑spinal CD68 protein

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↓spinal CD68 protein

191

↓dorsal horn Iba1 protein a,b,c↓ventral horn Iba1 protein

↑spinal IκBα, protein ↓spinal NF-κB, GFAP, TNF-α, Iba1, iNOS, nitrotyrosine protein

↑oligodendrocyte survival a,c↑neuronal survival a,c↑motor recovery

↓histological damage ↑motor recovery ↓apoptosis Not reported Saline i.v. 250 nmol (82 μg)/kg DHA i.v. CD1 mice Compression SCI Paterniti et al. (2014)

ALA, α-linolenic acid; Alb, albumin; ARA, arachidonic acid; CD, cluster of differentiation; COX, cyclooxygenase; CRP, c-reactive protein; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GFAP, glial fibrillary acidic protein; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; Iba, ionized calcium-binding adaptor molecule; IL, interleukin; iNOS, nitric oxide synthase; NF-κB, nuclear factor kappa light chain enhancer of activated B cell; OA, oleic acid; PL, phospholipid; PUFA, polyunsaturated fatty acid; SCI, spinal cord injury; TNF, tumor necrosis factor; WT, wildtype; a,b,c indicates treatment group represented in outcome columns (brain n-3 PUFA, primary outcome, inflammatory outcome)

a,c a,c

Not reported Acute i.v. 30 min post surgery +4 weeks diet post surgery Vehicle i.v. þ control diet a) 500 nmol (164 μg)/kg DHA i.v. þ control diet, b) saline i.v. þ 400 mg/ kg/d DHA/EPA p.o., c) 500 nmol (164 μg)/kg DHA i.v. þ 400 mg/kg/d DHA/EPA p.o. Compression SCI Lim et al. (2013b)

C57BL/6 mice

Treatment duration/time point Comparison Treatment PUFA treatment(s) Species Injury model Authors (year)

Table 2 (continued )

30 min following injury or daily injection for 9 days (motor testing only)

Inflammatory Outcome Non-Inflammatory outcome

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Brain n-3 PUFA

192

their associated SPM in modulating elements of the neuroinflammatory environment. Given the complexity of the interaction between different cell types in neuroinflammation, along with the potential modifying role of the peripheral immune system, animal models provide some advantages over cell culture models to study the interaction between dietary n-3 PUFA and inflammation in the brain. Diet is capable of changing the plasma concentrations of n-3 PUFA and SPM (Barden et al., 2014), and the levels of these components in the plasma are often used as a basis to select treatment doses in cell culture systems. It is not clear, however, how much diet, particularly in the short term, can influence brain composition of n-3 PUFA and SPM, and thus how relevant these doses may be to the brain. Moreover, a recent paper that established an adult microglial signature based on expression of 239 genes found that two of the most commonly used microglial cell lines, Bv2 and N9, do not express this signature, putting into question the generalizability of work with these and other cell lines to the brain (Butovsky et al., 2014). In this review, we will summarize the evidence for the role of n-3 PUFA in modulating neuroinflammation in animal models by updating and adding to our previous review, published in 2013 (Orr et al., 2013b).

2. Results 2.1. n-3 PUFA and neuroinflammation in ischemia or ischemia/ reperfusion Inflammation is a key component of stroke injury. We identified 16 studies (summarized in Table 1) that have investigated the role of n-3 PUFA in controlling inflammation following ischemia and ischemia and reperfusion (I/R). Three studies have investigated chronic effects of n-3 PUFA. Lalancette-Hébert and colleagues utilized the TLR2-fluc-GFP transgenic mouse, a mouse that is transgenically modified to be bioluminescent upon TLR2 activation, supplemented with DHA (0.7% of total diet weight) for 12 weeks. Compared to the low n-3 PUFA control, DHA supplementation decreases infarct size, microglia activation (as indicated by bioluminescence) and COX-2, IL6 and IL-1β protein expression following 1 h middle cerebral artery occlusion. This was correlated with increased striatal DHA (Lalancette-Hebert et al., 2011). This is in agreement with a study looking at perinatal supplementation, which showed that pups of dams supplemented with DHA and EPA during pregnancy and lactation experience a lower level of microglia activation and expression of COX-2, TNF-α, and IL-1β mRNA following ischemic brain injury (Zhang et al., 2010). Finally, Luo et al. utilized the fat-1 transgenic mouse to test the chronic effect of DHA on inflammation following I/R. The fat-1 mouse endogenously converts n-6 to n-3 PUFA, leading to high brain DHA concentrations (Orr et al., 2010). Following 20 min occlusion of the common carotid artery, the fat-1 mouse has reduced hippocampal TNF-α, IL-1β, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba1) protein levels compared to its wildtype control after 7 days of reperfusion (Luo et al., 2014). Sub-chronic studies have replicated the anti-inflammatory effects of n-3 PUFA observed in chronic exposure. Rats given daily DHA injections (500 nmol [164 μg]/kg/d i.p.) for 3 days prior to brain ischemia have diminished infarct sizes at 3 days postischemia (without reperfusion), accompanied by reduced microglia, neutrophil and macrophage labelling, and lower TNF-α, IL-1β and IL-6 mRNA levels (Chang et al., 2013). Daily EPA injections (500 mg/kg i.p., 4 weeks) prior to I/R also result in neuroprotection in gerbils, increasing neuronal survival in the hippocampus and

Table 3 Summary of studies investigating the effects of n-3 PUFA on aging and Alzheimer’s disease models. Species

PUFA treatment(s)

Comparison treatment

Treatment duration/ time point

Brain n-3 PUFA

Non-inflammatory outcome

Inflammatory outcome

Martin et al. (2002)

Aging (4 vs. 22 mo)

Wistar rats

Chow supplemented with 10 mg/d then 20 mg/d eEPA

Chow

3 weeks (10 mg/ day)þ 5 weeks (20 mg/ day)

Not reported

↑LTP ↓apoptotic markers

↓CX and HIP IL-1β

Maher et al. (2004)

Aging (4 vs. 22 mo)

Wistar rats

Chow supplemented with 10 mg/d then 20 mg/d eEPA

Chow

3 weeks (10 mg/ day)þ 5 weeks (20 mg/ day)

Not reported

↓apoptotic markers ↓neurotrophic factors

↓CX IL-1β protein 2CX IL-1RI protein ↑CX IL-4 protein

Lynch et al. (2007)

Aging (4 vs. 22 mo)

Wistar rats

Chow supplemented with 125 mg/d eEPA

Chow supplemented with MUFA (isocaloric)

4 weeks

Not reported

Aβ (i.c.v.) in aged rats (22 mo)

Wistar rats

Chow supplemented with 125 mg/d eEPA

Chow supplemented with MUFA (isocaloric)

4 weeks

Not reported

↑LTP

↓HIP IL-1β protein

Aβ (i.c.v.)

Wistar rats

Chow supplemented with 125 mg/d eEPA

Chow supplemented with MUFA (isocaloric)

4 weeks

Not reported

↑LTP

↓HIP IFN-γ, IL-1β protein ↑HIP PPARγ protein

Aging (3 vs. 22 mo)

Wistar rats

Chow supplemented with 125 mg/d eEPA

Chow supplemented with MUFA (isocaloric)

4 weeks

Not reported

Kelly et al. (2011)

Aging (4 mo vs. 20 mo)

Rats (Strain unspecified)

a) Chowþ EPA (200 mg/kg/d), b) chowþDPA n-3 (200 mg/ kg/d)

Chow þMUFA

8 weeks

a

↑CX total DHA a ↑CX total EPA a,b↑ CX total n-3 DPA

a,b

↑LTP a,b↑learning and memory (MWM) a,b↓apoptotic a,b markers ↓oxidative stress

a,b

Lebbadi et al. (2011)

3  Tg-AD mice (12 vs. 20* mo)

3  Tg-AD/ Fat-1 mice

3  Tg-AD/Fat1 on low n-3 diet

3  Tg-AD/WT on low n-3 diet

18 months

↑CX total DHA ↑ n-3/n-6 ratio

*↓in some AD markers

*↓CX GFAP protein

Moranis et al. (2012)

Aging (3– 5* vs. 19– 23 mo)

CD1 mice

N-3 adequate diet (fatty acids 10.7% LA, 1.6% ALA)

N-3 deficient diet (0.1% ALA of fatty acids)

3–5 months or 19–23 months

↑CX DHA

↓depressive behavior (FST)§ *↑spatial memory (YM) 2age-induced spatial memory loss (YM)

2CX IL-6 or IL-10 protein

Minogue et al. (2007)

↓HIP MHCII and CD40 ↓HIP IL-1β, IFN-γ protein ↓HIP IL-1β mRNA ↑HIP IL-4 protein and mRNA

↑HIP PPARγ protein

↓CX MHCII protein ↓HIP MHCII mRNA

a,b

193

Injury model

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Authors (year)

ALA, α-linolenic acid; Aβ, amyloid beta; AD, Alzheimer’s disease; CD, cluster of differentiation; CX, cortex; DHA, docosahexaenoic acid; DPAn-3, docosapentaenoic acid; EPA, eicosapentaenoic acid; eEPA, ethyl EPA; FST, forced swim test; GFAP, glial fibrillary acidic protein; HIP, hippocampus; IFN, interferon; IL, interleukin; LA, linoleic acid; LTP, long term potentiation; MHCII, major histocompability complex II; MWM, Morris water maze; MUFA, monounsaturated fatty acid; PPARγ, peroxisome proliferator activated protein γ; PUFA, polyunsaturated fatty acids; TNF, tumor necrosis factor; WT, wildtype; YM, y maze a,b,* indicates treatment group represented in outcome columns (brain n-3 PUFA, primary outcome, inflammatory outcome) § main effect of n-3 adequate vs. n-3 deprived diet (no effect of age)

↑HIP TNF-α mRNA 2HIP GFAP mRNA ↓spatial memory (MWM) ↓problem solving 2caudate nucleus task 2Aβ burden 27 weeks Corn oil TgCRND8 mice TgCRND8 mice Parrott et al. (2015)

Whole food diet containing 0.25% DHA (total diet weight)

↓HIP CD11b, IL-6, TNF-α mRNA 2HIP GFAP, IL1β mRNA ↑HIP astrocyte process length ↑spatial memory (YM) 2object recognition ↑DG c-fos ↑DHA, EPA 8 weeks Rapeseed oil, high oleic sunflower oil and palm oil (0.08% ALA of total diet weight) Controlþ Tuna oil (0.55% EPA, 0.36% DHA of total diet weight) C57BL/6 mice Aging (3 mo vs. 22 mo) Labrousse et al. (2012)

Table 3 (continued )

Inflammatory outcome Non-inflammatory outcome Brain n-3 PUFA Treatment duration/ time point Comparison treatment PUFA treatment(s) Species Injury model

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Authors (year)

194

reducing microglial activation (Okabe et al., 2011). Similarly, 6 weeks of daily DHA injections (500 nmol [164 μg]/kg/d i.p.) prior to I/R injury lowers infarct size, while also reducing leukocyte infiltration and IL-6 levels compared to control (Pan et al., 2009). This effect is dose-dependent, as 100 nmol (33 μg)/kg/d DHA is ineffective at lowering leukocyte infiltration and IL-6 protein. Similar results were reported with single acute injections of 100 nmol (33 μg) and 500 nmol (164 μg)/kg DHA either 1 h or 3 days prior to the ischemic injury (Pan et al., 2009). Six acute studies have demonstrated similar anti-inflammatory effects of n-3 PUFA on I/R models. Three separate studies report that i.v. injection of DHA (5–14 mg) 1 h after 2 h of ischemia in rats results in a decrease in infarct size 7 days post-reperfusion and improves neurological scores, while increasing GFAP protein expression, an astrocytic marker, in the cortex (Belayev et al., 2009, 2011; Eady et al., 2012a). This is also accompanied by decreases in CD68 protein, a marker of microglia and macrophages (Belayev et al., 2011; Eady et al., 2012a). A fourth study found that i.v. infusions (1 h and 12 h post-occlusion) of 21.5 mg/kg or 32.5 mg/kg of DHA and EPA, respectively, attenuates I/R-induced increases in expression of IL-1β, TNF-α, and nucleotide binding domain and leucine rich containing protein 3, a protein involved in IL-1β processing, while also reducing the microglia mRNA marker Arg1 (Zendedel et al., 2015). Complexing DHA to albumin appears to have an additive effect, where infusion of 5 mg of DHA complexed with 0.63 g of albumin causes a greater decrease in the microglia/ macrophage marker CD68 than DHA alone, in both young (Eady et al., 2012b) and aged rats (Eady et al., 2014). The mechanism by which n-3 PUFA may provide protection in these models is not agreed upon. One suggested mechanism is through the enzymatic conversion of n-3 PUFA to SPM, including Rv and protectins (Serhan, 2014). Within the mouse brain, I/R injury induces RvD1 production, with higher levels in the fat-1 mouse, which is protected against I/R injury, compared to its wildtype littermate (Luo et al., 2014). Further, acute injection of 5 mg of DHA 3 h post-ischemia increases production of NPD1 and its precursor compared to the saline control (Belayev et al., 2011). Direct i.v. infusion of 333 μg/kg of the stereoisomer of NPD1, aspirin‐triggered NPD1, 1 h post-reperfusion produces similar antiinflammatory effects as previous n-3 PUFA studies, increasing GFAP and reducing CD68 protein while reducing the infarct size (Bazan et al., 2012). Not all studies, however, show anti-inflammatory effects of n-3 PUFA in ischemic and I/R models. Black and colleagues reported that 135 min of i.v. infusion of 833 μg EPA 5 min prior to ischemia does not reduce the concentrations of pro-inflammatory mediators including PGE2 (Black et al., 1984). Moreover, a second study reported an increase in infarct size following administration of 500 nmol (164 μg) of DHA i.p. 1 h after reperfusion along with increased leukocyte infiltration and COX-2 mRNA expression 24 h post-reperfusion (Yang et al., 2007). Similar results were obtained following injection of ARA, but not stearic acid (Yang et al., 2007). The authors argue that the injection of PUFA, including DHA and ARA, results in increased oxidative damage following ischemic injuries. When looking at all the studies together, evidence appears to point to a neuroprotective effect of endogenously synthesized n-3 PUFA, dietary n-3 PUFA, or n-3 PUFA injection to reduce the inflammation related to animal models of ischemia and I/R injury. There are contradicting results regarding the effects of postischemia treatment, as one study (Yang et al., 2007) suggests possible damaging effects of n-3 PUFA. 2.2. n-3 PUFA and neuroinflammation in spinal cord injury Microglia and astrocyte activation is a major component of the

Table 4 Summary of studies investigating the effects of n-3 PUFA on Parkinson’s disease models. Injury Model

Species

PUFA treatment(s)

Comparison treatment

Treatment duration/time point

Brain n-3 PUFA

Non-inflammatory outcome

Meng et al. (2010)

MPP þ

C57BL/6 mice

Chowþ 0.8% eEPA

Chowþ 0.8% palm oil

6 weeks

↑ ST/FCX Total EPA and DPA 2ST/FCX Total DHA

2ST, FCXn DA 2 ST Bcl-2 mRNA ↓ST Bax, Caspase- 2ST cPLA2 and COX-2 3 mRNA mRNA

Muntane et al. (2010)

A53T α -synuclein transgenic mice

A53T α -synuclein trans- a) Low n-3 þ11.4% DHA Control (8% of fatty 6 months acid n-3) from genic mice (13% of fatty acid n-3), 6 months of b) Low n-3 (0.9% of fatty age acid n-3)

a

↑total DHA and EPA

a,b↓oxidative stress

Bousquet et al. (2011b)

MPTP (i.p.)

Fat-1 transgenic mice (C57BL/6 xC3H)

Fat-1 transgenic mice on high n-6/low n-3 diet (101.79:1 n6/n3 ratio)

6 months wildtype littermates on high n-6/ low n-3 diet (101.79:1 n6/n3 ratio)

↑CX DHA

2striatal or nigral dopaminergic injuryΨ

↓CX GFAP

Luchtman et al. (2012)

MPTP-P (s.c.)

C57BL/6 mice

Chowþ 0.8% eEPA

Chowþ 0.8% palm oil

6 weeks

↑CX EPA, DPA n-3 2CX DHA

↓hypokinesia and anxiety (RT, PT, OF) ↑ learning and memory (MWM)

↓striatal TNF-α, IFN-γ protein ↓midbrain IL10 protein 2striatal cPLA2, COX-2 mRNA°

Ji et al. (2012)

SN LPS (i.c.v.)

Sprague Dawley rats

15% fish oil diet (30% 15% corn oil diet fish oil as EPA and DHA)

2 weeks

Not reported

↓dopaminergic injury ↓nigral dopaminergic neuron ↓SN CD11b, TNF-α, ILdegeneration 1β p65 (NF-κB subunit) protein

Tian et al. (2015)

SN LPS (i.c.v.)

Sprague Dawley rats

Per kg body weight (route not specified):a) 25 μg RvD2 b) 50 μg RvD2 c) 100 μg RvD2

Not reported

3 days prior to Not reported LPS and 27 days post

b,c

Inflammatory outcome

a,b

2α-synuclein

↓rotational behavior (RT) neurons

b,c

↑dopaminergic

a,b2CX lectin and GFAP

a,b,c

↓SN CD11b protein

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Authors (year)

COX; cyclooxygenase; CD, cluster of differentiation; CX, cortex; DA; dopamine; DHA, docosahexaenoic acid; eEPA, ethyl EPA; EPA; eicosapentaenoic acid; FCX; frontal cortex; GFAP, glial fibrillary acidic protein; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MPPþ , 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MWM; morris water maze; NF-κB, nuclear factor kappa light chain enhancer of activated B cell; OF, open field; PLA, phospholipase; PT; pole test; PUFA, polyunsaturated fatty acids; RT; rotorod test; Rv, resolvin: SN, substantial nigra; ST, striatum; TNF, tumor necrosis factor a,b indicates treatment group represented in outcome columns (brain n-3 PUFA, non-inflammatory outcome, inflammatory outcome). °EPA lowered COX-2 mRNA compared to palm oil in saline (control) injected animals. Ψ protection from nigral dopaminergic injury was correlated to brain DHA levels (secondary analysis). n EPA increased striatal dopamine in saline injected group.

195

196

Table 5 Summary of studies investigating the effects of n-3 PUFA on lipopolysaccharide models. Authors (year)

Injury model

Species

PUFA treatment(s)

Comparison treatment

Treatment duration/time point

Brain n-3 PUFA

Non-inflammatory outcome

Inflammatory outcome

Kavanagh et al. (2004)

Systemic LPS (i.p.)

Wistar rats

a) Chow þ50 mg/d eEPA, b) chowþ 50 mg/d eGLA, c) chowþ 50 mg/d eEPA and eGLA

Chow

4 weeks

Not reported

a,b,c

a,b,c

Lonergan et al. (2004)

Systemic LPS (i.p.)

Wistar rats

Chow supplemented with 500 mg/d eEPA

Chow

4 weeks

Not reported

↑LTP ↓apoptotic markers

↓HIP IL-1β protein

Mingam et al. (2008)

Systemic LPS (i.p.)

CD1 mice

6% peanut þ rapeseed oil (n-6 þ n-3) diet

6% peanut oil (n-6) diet

Gestation þ 8 weeks postnatal

↑CX DHA

↓social interaction 2food intake

2HIP IL-6 mRNA

Orr et al. (2013a)

LPS i.c.v

C57BL/6 mice

8% safflowerþ2% fish oil

10% safflower diet

9 weeks

↑HIP total DHA 2HIP FFA DHA

↓HIP COX-2 mRNA 2HIP IL-1β, GFAP, cPLA2, CCL3, iNOS, mPGES, RelB, CD11b, CD45, CCL2, CYBB, TNF-α mRNA

LPS i.c.v.

C57BL/6 mice

a) 40 μg i.c.v. DHA, b) 1 μg i.c.v. 17 SHpDHA

a

24 h infusion post surgery

b

a,b

LPS i.c.v

Fat-1 transgenic mice (C57BL/6  C3H)

Fat-1 transgenic mice on 10% safflower diet

Wildtype littermate on 10% safflower diet (n-3 deficient)

12 weeks

↑HIP total and FFA DHA

↓HIP IL-1β, GFAP, cPLA2, COX-2, CCL3, iNOS, mPGES, RelB, CD11b, CD45, CCL2, CYBB, TNF-α mRNA ↓HIP GFAP, Iba1, FJb protein

LPS i.c.v

Fat-1 transgenic mice (C57BL/6  C3H)

Fat-1 transgenic mice on 10% safflower diet

Wildtype littermate on 8% safflower dietþ 2% fish oil

12 weeks (wildtype were on fish oil for only 9 weeks)

2HIP total and FFA DHA

↑HIP mPGES mRNA 2HIP IL-1β, GFAP, cPLA2, COX-2, CCL3, iNOS, mPGES, RelB, CD11b, CD45, CCL2, CYBB, TNF-α mRNA

Systemic LPS (i.p.)

Fat-1 transgenic mice (C57BL/6  C3H)

Fat-1 transgenic mice on standard diet (4.8% of total fatty acids n-3 PUFA)

Wildtype littermate on standard diet (4.8% of total fatty acids n-3 PUFA)

3–5 months

2HIP total DHA ↑HIP total DPA n-3 and EPA

↑HIP NPD1

↑HIP IL-10, IL-4 protein

a,c

↑HIP PPARγ protein

a,b,c

2HIP IL-1β protein

↓HIP IL-1β, CCL3, TNF-α, CD11b, CD45, CYBB mRNAb↓HIP GFAP, CD11b mRNA a,b2HIP GFAP, cPLA2, COX-2, iNOS, mPGES, RelB, CCL2, CD11b mRNAa2HIP GFAP, CD11b mRNA

↑learning and memory ↑HIP COX-2, TGF-β1, mPGES-1 and CX3CL1 mRNA ↓HIP IL-1β mRNA 24 h post LPS 2HIP (YM) ↑food consump- TNF-α, IL-6, IL-10, CX3CL1 mRNA 24 h post LPS ↑HIP CD36 and MHCII protein 24 h post LPS tion 2body weight ↑HIP IL-10 mRNA 2 h post LPS 2HIP TNF-α, IL-1β and IL-6 mRNA 2 h post LPS loss

17-HDHA, 17-hydroxy-DHA; CCL, chemokine (c-c motif) ligand; aCSF, artificial cerebrospinal fluid; CD, cluster of differentiation; CX3CL, chemokine (c-x3-c motif) ligand; COX, cyclooxygenase, CX, cortex; CYBB, cytochrome b-245 beta polypeptide DHA, docosahexaenoic acid; DPA, docosapentaenoic acid, eEPA, ethyl EPA; eGLA, ethyl gamma-linolenic acid; EPA, eicosapentaenoic acid; FFA, free fatty acid; FJ, Fluoro-jade; GFAP, glial fibrillary acidic protein; HIP, hippocampus; Iba, ionized calcium-binding adapter molecule; IL, interleukin; LPS, lipopolysaccharide; LTP, long term potentiation; MHC, major histocompatibility complex n, omega; NOS, nitric oxide synthase; NP, neuroprotectin; PGES, prostaglandin E synthase PLA, phospholipase; PPAR, peroxisome proliferator activated protein, PUFA, polyunsaturated fatty acids; RelB, nuclear factor-κB subunit; TGF, transforming growth factor; TNF, tumor necrosis factor; YM, y maze a,b indicates treatment group represented in outcome columns (brain n-3 PUFA, non-inflammatory outcome, inflammatory outcome)

M.-O. Trépanier et al. / European Journal of Pharmacology 785 (2016) 187–206

Delpech et al. (2014)

CSF i.c.v.

↑LTP

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pathophysiology of spinal cord injury. During spinal cord injury, leukocytes are also recruited from the blood to the site of the injury where they release various pro-inflammatory lipid mediators and cytokines, exacerbating the innate inflammatory response that leads to extensive tissue damage potentially contributing to loss of function (Donnelly and Popovich, 2008). Nine studies (Table 2) have evaluated the outcome of intravenous n-3 PUFA administration either before or following spinal cord injury on neuroinflammatory markers. It was reported that 250 nmol (82 μg)/kg DHA administered i.v. 30 min after spinal hemisection reduces lesion size, and increases neuronal survival and motor recovery, despite its lack of effect on CD68 protein levels (King et al., 2006). In contrast, injection of ARA in the same model exacerbates neuroinflammation and decreases cell viability (King et al., 2006). The lack of anti-inflammatory effect of acute DHA is in agreement with results reported by 2 separate studies, which find that i.v. injection of 250 nmol (76 or 82 μg)/kg of either EPA or DHA 30 min post spinal compression does not decrease protein concentrations of TNF-α, IL-1β or IL-6 (Hall et al., 2012; Lim et al., 2010). However, Hall et al. (2012) did observe a decrease in JT1, a marker of neutrophil infiltration, following DHA administration. Similar to the report of King et al. (2006), Lim et al. (2010) show EPA administration increases cell survival and motor recovery even though there is no effect on CD68 expression. While the studies above reported no effect on inflammatory markers of n-3 PUFA administered following spinal injury, other studies show reduced pro-inflammatory markers following i.v. infusion of n-3 PUFA. In separate studies, i.v. injection of 250 nmol (82 μg)/kg DHA following spine compression reduced COX-2 (Huang et al., 2007), GFAP, TNF-α and nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) protein concentrations (Paterniti et al., 2014), while also decreasing activated microglial markers CD68 and Iba1 (Huang et al., 2007; Paterniti et al., 2014). The effect of chronic oral administration of n-3 PUFA following spinal compression was assessed in two studies, with mixed results. Huang and colleagues reported that 400 mg/kg of DHA p.o. for 4 weeks following injury, in combination with an acute injection of 250 nmol (82 μg)/kg of DHA i.v. 30 min after the injury reduces microglia markers compared to control and appears to have an additive effect compared to injection alone (Huang et al., 2007). A second study, however, found that oral intake of 400 mg/ kg of DHA alone for 4 weeks only reduces microglia activation in the ventral horn of the spinal cord with no effect on motor control, while injection of 500 nmol (164 μg)/kg of DHA i.v. alone or in combination with oral DHA supplementation reduces microglia activation in both ventral and dorsal horns and increases motor recovery (Lim et al., 2013b). Three studies evaluated n-3 PUFA administration prior to spinal cord injury. While acute injection of 250 nmol (82 μg)/kg DHA in rats either 1 h or 1 week prior to spinal compression had no effect on GFAP, CD68 and CD11b (Figueroa et al., 2012), 250 nmol (70 μg)/kg of ALA i.v. 30 min prior to spinal cord ischemia appeared to decrease NF-κB staining (Lang-Lazdunski et al., 2003). The transgenic fat-1 mouse, with higher brain DHA, had attenuated spinal cord injury‐induced Iba1 and IL-6 protein increases compared to wildtype littermate (Lim et al., 2013a). Taking all of these studies together, it is difficult to conclude on the anti-inflammatory properties of n-3 PUFA in spinal cord injury. n-3 PUFA have variable effects on astrocytic and microglial markers in spinal cord injury, despite the fact that n-3 PUFA appear to increase motor control recovery and cell survival in these models. 2.3. n-3 PUFA and neuroinflammation in aging Aging is associated with cognitive decline, as well as activated

197

microglia (Mosher and Wyss-Coray, 2014) and reactive astrocytes (Salminen et al., 2011), which release pro-inflammatory cytokines. Alzheimer’s disease is associated with similar neuroinflammatory markers, as well as neuronal loss and accumulation of Aβ plaques and neurofibrillary tangles (Glass et al., 2010). There are 9 studies evaluating the effects of n-3 PUFA on neuroinflammation induced by aging or Alzheimer's pathology (Table 3). When comparing young vs. aged rats, 3 week dietary supplementation of 10 and then 20 mg/kg of ethyl EPA in aged rats reduces the IL-1β protein concentration to levels present in young rats (Maher et al., 2004; Martin et al., 2002) while also elevating the anti-inflammatory cytokine IL-4 in the cortex (Maher et al., 2004). This is in agreement with the observation that supplementation of 125 mg/day of ethyl EPA for 4 weeks lowers CD40, IL1β and IFN-γ (Lynch et al., 2007) while elevating IL-4 (Lynch et al., 2007) and PPARγ (Minogue et al., 2007) in the hippocampus of aged rats. Similarly, chronic (8 week) dietary tuna oil composed of 0.55% EPA and 0.36% DHA (% of total diet weight), prevents ageinduced elevations of hippocampal TNF-α and monocytic marker CD11b protein levels, whereas GFAP and IL-1β increase despite supplementation (Labrousse et al., 2012). A separate study demonstrates that supplementing aged mice with 200 mg/kg/d of EPA elevates cortical DHA, EPA and n-3 docosapentaenoic acid, while n-3 docosapentaenoic acid supplementation only raises cortical n-3 docosapentaenoic acid. Despite this difference, both treatments decrease levels of major histocompatibility complex II, a protein found on antigen presenting cells, in the hippocampus and cortex of n-3 PUFA supplemented compared to control chow groups (Kelly et al., 2011). Moranis et al. (2012) however, report no effect of an n-3 PUFA adequate diet consisting of ALA in aged mice on levels of pro and anti-inflammatory cytokines (IL-6 and IL-10 respectively) and age-induced memory deficits, despite the fact that the n-3 PUFA adequate diet increases cortical DHA and decreases depressive behavior compared to an n-3 PUFA deficient diet. When challenged with Aβ i.c.v., aged mice supplemented with 125 mg/kg ethyl EPA have lower IL-1β (Lynch et al., 2007) and higher PPARγ compared to those on a control diet (Minogue et al., 2007). Twenty month old 3  Tg-AD mice, a transgenic mouse model of Alzheimer’s disease, have a reduction in GFAP protein in the parieto-temporal cortex when crossed with the fat-1 mouse (Lebbadi et al., 2011). Administration of n-3 PUFA has not always yielded positive results in Alzheimer’s Disease models. When supplemented with 0.25% DHA (% of total diet weight) for 27 weeks, the TgCRND8 transgenic mouse, which overexpresses two mutated forms of the amyloid precursor protein gene, demonstrates poor spatial memory in the Morris water maze and elevated TNF-α gene expression in the hippocampus compared to those receiving corn oil. It should be noted that DHA was delivered in a whole food diet, which also contained vitamins and phytochemicals (Parrott et al., 2015). 2.4. n-3 PUFA and neuroinflammation in Parkinson’s disease Parkinson’s disease has a neuroinflammatory component, with evidence of activated microglia, and high pro-inflammatory cytokine and NF-κB levels in both postmortem human samples and in vivo animal models (Tansey and Goldberg, 2010). n-3 PUFA may target neuroinflammation in Parkinson’s disease models, along with other potential mechanisms, including oxidative stress and increased neurotrophic factors (Bousquet et al., 2011a) (Table 4). Six studies were identified that investigate the effects of n-3 PUFA on neuroinflammation in Parkinson’s disease models (Table 5). When supplementing mice with a diet containing 0.8% ethyl EPA (% of total diet weight), Luchtman et al. (2012) observed a reduction in s.c. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-

↓HC IL-1 mRNA Not reported 2acetylcholine release ↑NGF ↑learning and memory (8ARM) 0.8% (v/w) palm oil 7 weeks prior surgery Long–Evans 0.8% (v/w) eEPA rats

8ARM, 8-arm radial maze; ARA, arachidonic acid; eEPA; ethyl eicosapentaenoic acid; eGLA, ethyl gamma-linolenic acid; EPM, elevated plus maze; IL, interleukin; MWM; morris water maze; NGF, nerve growth factor; PG, prostaglandin; PUFA, polyunsaturated fatty acids a,b,c indicates treatment group represented in outcome columns (brain n-3 PUFA, non-inflammatory outcome, inflammatory outcome)

IL-1β (i.c.v.) Song et al. (2008)

Taepavarapruk and Song IL-1β i.c.v. (2010)

↓HIP PGE2a↓ amygdala PGE2a↓ PGE2a↓ amygdala, hypothalamus IL-10 protein

a,b

a ↓memory loss (MWM) a↓anxiety (EPM)

Not reported 7 weeks 5% palm oil diet a) 4.5% palm oil þ0.5% eEPA b) 4.5% palm oil þ0.5% eGLA c) 4% palm oilþ 1% ARA-rich oil diet

↓memory loss (MWM) Not reported 5% coconut oil diet 7 weeks

a) 5% soybean,4.8% coconut oil þ 0.2% eEPA, b) 4% coconut oilþ 1% eEPA diet Wistar rats IL-1β (i.c.v.) Song and Horrobin (2004)

Wistar rats

b b

↓brain PGE2

Inflammatory outcome Comparison treatment Species Injury model

There are five studies (Table 5) on the effects of n-3 PUFA on the in vivo brain response to LPS. Four of these studies administered LPS peripherally by i.p. injection. Kavanaugh et al. reported that mice receiving 50 mg/d of either ethyl EPA, ethyl gamma linolenic acid (GLA) or a combination of both fatty acids for 4 weeks are protected from LPS-induced (100 μg/kg i.p.) decreases in anti-inflammatory cytokines IL-4 and IL-10 in the hippocampus, while only ethyl EPA and ethyl EPAþ ethyl GLA attenuate the decrease in PPARγ protein. None of the treatments reduced hippocampal IL-1β protein concentration (Kavanagh et al., 2004). Similarly, a n-3 PUFAþn-6 PUFA diet (6% total weight made of rapeseed and peanut) fed to dams from gestation through to 8 weeks postnatal does not attenuate hippocampal IL-6 mRNA response of pups to 30 mg/kg LPS i.p. compared to n-6 PUFA-only diet (6% peanut) (Mingam et al., 2008). A separate study, however, reported that 500 mg/d ethyl EPA for 4 weeks, decreases hippocampal IL-1β, along with apoptotic cell markers upon LPS (100 μg/kg i.p.) administration (Lonergan et al., 2004). Finally, 24 h following 125 μg/kg of LPS i.p., fat-1 transgenic mice have attenuated LPS-induced increases in IL-1β mRNA compared to their wildtype littermates. However, fat-1 mice also have augmented LPS-induced increases in COX-2, membrane associated PGE synthase-1, transforming growth factor β1 and chemokine (cx3-c) ligand (CX3CL) 1. The authors argued that increases in these genes reflect an anti-inflammatory phenotype, where the fat-1 mouse has a higher proportion of M2 phenotype microglia 24 h post-LPS (Delpech et al., 2014). The fifth study administered 5 μg of LPS directly into the left lateral ventricle of the brain, which minimizes systemic effects

Table 6 Summary of studies investigating the effects of n-3 PUFA on IL-1β models.

2.5. n-3 PUFA and neuroinflammation with lipopolysaccharide

PUFA treatment(s)

Treatment duration/time point

Brain n-3 PUFA

(MPTP) induced increases in striatal TNF-α and IFN-γ protein. Midbrain IL-10 protein is also reduced by ethyl EPA treatment, while expression of COX-2 and calcium-dependent cytosolic PLA2, enzymes involved in inflammatory signaling, are unaffected. Similarly, Meng and colleagues found no difference in striatal COX-2 or calcium-dependent cytosolic PLA2 mRNA expression following 6 weeks of 0.8% ethyl EPA prior to i.c.v. injection of 1-methyl-4phenylpyridinium (MPPþ), the active metabolite of MPTP. Both studies achieved increases in brain EPA, but not brain DHA with p.o. ethyl EPA (Luchtman et al., 2012; Meng et al., 2010). In a third study, fat-1 transgenic mice with raised cortical DHA, have lower levels of the astrocytic marker GFAP compared to their wildtype littermates after MPTP-induced injury (Bousquet et al., 2011b). Injecting LPS directly into the substantia nigra causes dopinergic neuron injury and a neuroinflammatory response, similar to Parkinson’s disease. Feeding a diet containing 15% fish oil (% of total diet weight) to Sprague Dawley rats for 2 weeks minimizes dopaminergic injury, while also reducing OX42 (also known as CD11b) protein, a monocytic marker, as well as TNF-α and IL-1β (Ji et al., 2012). In the last study, the authors evaluated n-3 PUFA supplementation in A53T α –synuclein transgenic mice, a transgenic model of Parkinson’s disease expressing mild symptoms. Supplementation with a diet containing 13% n-3 PUFA of total fatty acids does not affect lectin, a microglial marker, or GFAP-positive cell counts (Muntane et al., 2010). Injecting 25, 50, or 100 μg/kg of RvD2 (route of administration not specified) for 3 days prior to LPS injection followed by 27 daily injections decreased the LPS induced increases in CD11b protein. The 25 μg/kg dose, however, was ineffective at reducing apo-morphine induced rotational behavior (Tian et al., 2015). Overall, the supplementation of n-3 PUFA does not appear to affect enzymes of the arachidonic cascade in Parkinson’s disease models. It is does appear, however, that n-3 PUFA does reduce cytokine production and may reduce astrocyte and microglia activation.

Non-inflammatory outcome

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Authors (year)

198

b ↓activated microglia b↓rod microglia b↑ramified microglia a

Not reported Saline i.p. a) 100 ng AT-RvD1 i.p., b) 100 ng RvE1 i.p. C57BL/6 mice Harrison et al. Traumatic (2015) brain injury

Daily for 7 days starting 3 days before injury

C57BL/6 mice Traumatic brain injury Pu et al. (2013)

AT, aspirin triggered; CA, cornu ammonis, CD, cluster of differentiation; COX, cyclooxygenase; CT, cylinder test; CX, cortex, DHA, docosahexaenoic acid; DPA, docosapentaenoic acid, EPA, eicosapentaenoic acid; FF, foot fault; Iba, ionized calcium-binding adapter molecule; IL, interleukin; MWM, morris water maze; NOS, nitric oxide synthase; PUFA, polyunsaturated fatty acids; Rv, resolvin; TNF, tumor necrosis factor; WH, wire hang a,b,c indicates treatment group represented in outcome columns (brain n-3 PUFA, non-inflammatory outcome, inflammatory outcome)

↓CX Iba1 COX-2 protein ↓CX IL-1α, IL-1β, TNF-α, COX-2 INOS mRNA ↑sensorimotor control (FF, WH, CT) ↑learning and memory (MWM) 2lesion volume ↑CA3 neuronal survival ↓myelin injury ↑nerve conductance ↑total brain DHA, EPA and n-3 DPA 2 months prior Low n-3 diet (0.5% n-3 PUFA of injury total diet weight) DHA and EPA supplemented diet (15 g/kg of diet)

↓motor deficit a↓learning and memory (OR) b↑sleep 2righting reflex

c

c ↓axon injury c↓apoptosis c↑learning and memory (MWM)

30 days prior injury Not reported No treatment Per kg per day: a) 4 mg DHA, b) 12 mg DHA, c) 40 mg DHA Traumatic brain injury Mills et al. (2011)

Sprague Dawley rats

↓CD68 protein

Inflammatory outcome Non-inflammatory outcome Treatment duration/ Brain n-3 PUFA time point Comparison treatment PUFA treatment(s) Species Injury model Authors (year)

Table 7 Summary of studies investigating the effects of n-3 PUFA on traumatic brain injury models.

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that i.p. injection of LPS may have (Orr et al., 2013a). C57BL/6 mice supplemented with 2% fish oil (% of total diet weight) for 9 weeks have elevated hippocampal total phospholipid DHA, but show no changes in the non-esterified fatty acid pool. Out of a panel of inflammatory markers, only hippocampal COX-2 mRNA is decreased by dietary fish oil supplementation upon LPS administration. The fat-1 mouse, which has both elevated total and nonesterified DHA in the hippocampus compared to the wildtype littermate, shows attenuated LPS-induced mRNA expression of a panel of pro-inflammatory genes including IL-1β, GFAP, COX-2, and CD45. When wildtype littermates are switched to a 2% fish oil diet for 9 weeks from weaning until surgery, phospholipid and non-esterified DHA reaches the same concentration as in fat-1 mice, and gene expression profiles are similar with the exception of higher hippocampal expression of membrane PGE synthase mRNA in the fat-1 mice (Orr et al., 2013a). This suggests the possibility that the non-esterified pool may be the important pool for regulating neuroinflammation. The authors concluded the study by evaluating the effect of infusing either 40 μg of DHA or 1 μg of 17S-hydroperoxy DHA (NPD1 precursor), i.c.v. immediately following LPS injection for 24 h. While only 17S-hydroperoxy DHA infusion increases NPD1 concentrations, both treatments decrease LPS-induced pro-inflammatory markers including TNF-α and IL-1β. 17S-hydroperoxy DHA appears to be more potent as 1 μg decreases CD11b and GFAP mRNA expression, which 40 μg DHA was unable to do. Unlike the transgenic and feeding approaches, i.c.v. administration of DHA or 17S-hydroperoxy DHA does not modulate ARA cascade enzymes COX-2 and calcium-dependent cytosolic PLA2 (Orr et al., 2013a). 2.6. n-3 PUFA and neuroinflammation in i.c.v. IL-1β We identified three studies that investigated the effect of n-3 PUFA on neuroinflammation induced by i.c.v. injection of IL-1β (Table 6). Supplementing rats for seven weeks with 1% ethyl EPA (% of total diet weight) prior to injection of IL-1β (15 ng i.c.v.) reduces not only memory deficits in the Morris water maze, but also brain PGE2 compared to the control coconut oil supplementation. However, supplementation of 0.2% EPA or 5% soybean oil is ineffective at attenuating the effects of i.c.v. IL-1β (Song and Horrobin, 2004). In a comparable study, 0.5% of either ethyl EPA or ethyl GLA (% of total diet weight) for 7 weeks prior to IL-1β administration (15 ng i.c.v.) reduces hippocampal PGE2. This study finds EPA is more effective than GLA at reducing IL-1β-induced amygdaloid PGE2 concentration and elevating IL-10 while also decreasing anxiety and memory deficits (Song et al., 2008). Finally, Taepavarapruk and Song (2010) also reported anti-inflammatory properties of ethyl EPA in the i.c.v. IL-1β model (15 ng i.c.v.), where 0.8% ethyl EPA (% of total diet weight) for 7 weeks reduced IL-1β induction of IL-1 mRNA, even though it did not alter acetylcholine concentrations. 2.7. n-3 PUFA and neuroinflammation in traumatic brain injury Traumatic brain injury is associated with an increase in proinflammatory cytokine production, including IL-1β and TNF-α, and also is marked by increased microglia activation (Mayer et al., 2013; Woodcock and Morganti-Kossmann, 2013). Three studies (Table 7) have evaluated the anti-neuroinflammatory properties of n-3 PUFA in traumatic brain injury models. Supplementing mice with a DHA- and EPA-enriched diet (1.5% of total diet weight) 60 days prior to controlled cortical impact decreases IL-1α, IL-1β and TNF-α mRNA expression following the injury compared to mice fed a low n-3 PUFA control. Mice on a high n-3 PUFA diet also exhibit lower COX-2 mRNA and protein concentrations following controlled cortical impact (Pu et al., 2013). A separate study found

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Table 8 Summary of studies investigating the effects of n-3 PUFA on neuropathic pain models. Injury Model

Species

Xu et al. (2013b)

Chronic constriction injury

Xu et al. (2013a)

Chronic constriction injury

PUFA Treatment(s)

Comparison Treatment

Treatment Duration/ Brain n-3 Time point PUFA

Non-Inflammatory Outcome

Inflammatory Outcome

CD1 mice 300 ng NPD1 s.c. perisurgical

Vehicle perisurgical

1 week prior to surgery

Not reported

↓mechanical allodynia ↓on going pain ↓autotomy ↓spinal LTP ↓axonal injury

↓spinal cord dorsal horn Iba1 protein ↓spinal cord dorsal horn GFAP, IL-1β and CCL2 mRNA

CD1 mice 100 ng RvE1 i.t.

Vehicle i.t.

Daily for 3 days post-injury

Not reported

↓mechanical allodynia 2heat hyperalgesia

↓dorsal horn Iba1 and GFAP mRNA ↓dorsal horn TNF-α protein

CCL, chemokine (c-c motif) ligand; GFAP, glial fibrillary acidic protein; Iba, ionized calcium-binding adapter molecule; IL, interleukin; LTP, long term potentiation; NP, neuroprotection, PUFA, polyunsaturated fatty acids; Rv, resolvin; TNF, tumor necrosis factor

Table 9 Summary of studies investigating the effects of n-3 PUFA on diabetes model. Authors (year)

Injury model

Species

PUFA treatment(s)

Comparison treatment

Treatment duration/ time point

Brain n-3 PUFA

Non-inflammatory outcome

Inflammatory outcome

Alvarez-Nölting et al. (2012)

STZ (i.p.)

Wistar rats

Chow plus 13.3 mg/ kg/d DHA by gavage

ChowΨ

12 weeks

Not reported

↓HIP NF-κB protein 2blood glucose and glycated hemoglobin ↑HIP neurogenesis ↓HIP neuronal apoptosis ↓HIP oxidative stress ↑learning and memory (MWM)

Jia et al. (2014)

STZ (i.p.)

Sprague Dawley rats

4% fish oil (1.2% EPA þ DHA)

Chow

1 week prior to STZand 5 week post STZ

Not reported

2blood glucose ↓HIP oxidative stress ↑learning and memory (MWM)

↓HIP TNF-α mRNA ↓HIP pIKKβ, TNF-α, NF-κB proteins ↑HIP IκBα protein

DHA, docosahexaenoic acid, EPA, eicosapentaenoic acid; HIP, hippocampus; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; MWM, morris water maze; NF-κB, nuclear factor kappa light chain enhancer of activated B cell; STZ, PUFA, polyunsaturated fatty acids; STZ, streptozotocin; TNF, tumor necrosis factor Ψ

Insulin-treated rats were also included in the study and were similar to DHA-only treated rats in all measures excluding weight, glycemic control, and oxidative stress.

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Authors (year)

Table 10 Summary of studies investigating the effects of n-3 PUFA on other neuroinflammatory models. Injury model

Species

PUFA treatment(s)

Comparison treatment

Treatment duration/time point

Brain n-3 PUFA

Non-inflammatory outcome

Inflammatory outcome

Lynch et al. (2003)

Whole body irradiation

Wistar rats

a) Chow þ250 mg/d eEPA, b) chowþ 500 mg/d eEPA

chow

4 weeks prior to irradiation

Not reported

a,b

a,b ↓HIP IL-1β, IL-1RI, IL-1RAcP protein a,b2HIP IRAK protein phosphorylation ratio a↑HIP IL-10 protein

Song et al. (2009)

Olfactory bulbectomy (depression)

Sprague Dawley rats

1% eEPA diet

1% palm oil diet

7 weeks

Not reported

↓depressive-like symptoms (MWM and OF)

↓hypothalamus cPLA2 mRNA and activity

Crupi et al. (2012)

BAFF transgenic mice (lupus and Sjogren’s syndrome)

BAFF transgenic mice

N-3 supplemented diet (1.54% of fatty acids n-3 PUFA)

Control (0% of fatty acids n-3 PUFA)

12 weeks

Not reported

↑neurogenesis ↑LTP

↓HIP CD68 protein

Terrando et al. (2013)

Surgically induced cognitive decline

C57BL/6 mice

100 ng AT-RvD1 i.p.

Vehicle i.p.

Prior to incision

Not reported

↓plasma LXA4, IL-6, AST protein ↑LTP ↑memory retention (FTC)

↑HIP GFAP area

Yip et al. (2013)

G93A-SOD1 (ALS)

G93A-SOD1

300 mg/kg/d eEPA and 43 mg/kg/d eDHA

Control diet

From 14 to 20 weeks

↑spinal DHA ↑Brain DHA and EPA

2disease progression in symptomatic mice ↑disease progression in pre-symptomatic ↑spinal vacuoles 2neuron morphology ↑lipid peroxidation

↓spinal GFAP, Iba1, and CD11b protein

Keleshian et al. (2014)

NMDA-induced excitotoxicity

a) N-3 adequate (4.6% of diet n-3 PUFA), b) fish oil (9.4% of diet n-3 PUFA)

N-3 deficient (0.2% of diet n-3 PUFA)

15 weeks

↑DHA

a,b

a,b 2IL-1β, cPLA2, sPLA2, COX-1, COX-2 and GFAP protein a,b2sPLA2 activity a,b↑cPLA2 activity in saline

↓apoptotic markers

2BDNF, NGF, iPLA2 protein a,b↓iPLA2 activity b↓body weight

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Authors (year)

ALS, amyotrophic lateral sclerosis; AST, aspartate transaminase; AT, aspirin-triggered; BDNF, brain derived neurotrophic factor; CD, cluster of differentiation; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; eDHA; ethyl DHA; eEPA, ethyl EPA; eGLA, ethyl GFAP, glial fibrillary acidic protein; HIP, hippocampus; FTC, fear conditioning test; Iba 1, ionized calcium-binding adaptor molecule; IL, interleukin; IL, interleukin; IRAK, IL-1 receptor-associated kinase; LTP, long term potentiation; LX, lipoxin; MWM, Morris water maze; n, omega; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; OF, open field; PUFA, polyunsaturated fatty acids; PLA, phospholipase a,b indicates treatment group represented in outcome columns (brain n-3 PUFA, primary outcome, inflammatory outcome.

201

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that following controlled cortical impact, CD68 protein levels are lower in mice consuming 40 mg/kg of DHA compared to no supplementation (Mills et al., 2011). Traumatic brain injury by midline fluid percussion induces cognitive impairment and motor deficits, while increasing activated microglia. The administration of 100 ng of aspirin-triggered RvD1 i.p., an SPM derived from DHA, for 7 days starting 3 days before the percussion reduced the injury induced cognitive impairment and motor deficit, but did not reduce microglia activation. RvE1, an SPM derived from EPA, however, did reduce traumatic brain injury induced microglia activation, while not having any effects on the cognitive impairments and motor deficits (Harrison et al., 2015). 2.8. n-3 PUFA and neuroinflammation in neuropathic pain Neuropathic pain is a disorder associated with a lesion of a nerve in either the peripheral or central nervous system (Baron, 2009; Cohen and Mao, 2014). Microglia are present in both acute and chronic neuropathic pain (Schomberg and Olson, 2012), while pro-inflammatory cytokines such TNF-α and IL-1β are thought to modulate pain responses (Cohen and Mao, 2014). Two studies were identified that evaluated the response of neuroinflammation following n-3 PUFA bioactive mediator treatment in a neuropathic pain model (Table 8). Injection of 300 ng of NPD1 at the site of injury immediately following chronic constriction of the sciatic nerve lowers the concentration of CCL2, a chemotractant for microglia, and microglia activation in the spinal cord dorsal horn (Xu et al., 2013b). Similar protection was obtained with 3 days of intrathecal injection of 100 ng of RvE1, following injury. RvE1 decreases pro-inflammatory Iba1 and GFAP mRNA expression and TNF-α protein concentration (Xu et al., 2013a). 2.9. n-3 PUFA and neuroinflammation in diabetes There is evidence that diabetes is linked with increased neuroinflammation, including NF-κB induction (Cai, 2013). Moreover, diabetics often experience diabetic neuropathic pain, which itself is associated with neuroinflammation including microglial activation (Wang et al., 2014a). Two studies investigated whether DHA was anti-neuroinflammatory in the streptozotocin (STZ) diabetic rat model (Table 9). STZ is a toxin that targets pancreatic beta cells, inducing diabetes. Rats gavaged with 13.3 mg/kg/d of DHA for 12 weeks prior to STZ (i.p.) have decreased hippocampal NF-κB and memory deficits despite elevated blood glucose levels, which were not impacted by DHA treatment (Alvarez-Nolting et al., 2012). Likewise, Jia et al. (2014) supplemented Sprague–Dawley rats with 4% fish oil (% of total diet weight) starting 1 week prior to STZ injection and continuing 5-weeks post-STZ, and show that supplementation attenuates STZ-induced TNF-α mRNA and protein increases in the hippocampus. Rats receiving fish oil performed better in the Morris water maze, indicating improved memory, even though blood glucose levels remained high (Jia et al., 2014). 2.10. n-3 PUFA and neuroinflammation in other models Several studies have reported on the anti-inflammatory effects of n-3 PUFA in other models (Table 10). Radiotherapy is a common therapeutic strategy against brain tumors, and it is associated with cognitive dysfunction and increases in pro-inflammatory cytokines mRNA such as IL-1β and TNF-α (Ballesteros-Zebadua et al., 2012; Kyrkanides et al., 1999). Lynch et al. observed that 4-week supplementation of 250 or 500 mg/d of ethyl EPA attenuates the increase of pro-inflammatory cytokines in the hippocampus of rats, including IL-1β, IL-1RI, IL-1RAcP, induced by whole body irradiation. Interestingly, the lower dose of 250 mg/d also raises IL-10

concentration (Lynch et al., 2003). Olfactory bulbectomy has been proposed as a model of depression in rats (Kelly et al., 1997), and presents with changes in immunity (Leonard and Song, 2002) and increased brain pro-inflammatory cytokines (Myint et al., 2007). Olfactory bulbectomized rats supplemented with 1% ethyl EPA (% of total diet weight) for 7 weeks demonstrate lower induction of calcium-dependent cytosolic PLA2 mRNA expression and protein activity compared to rats supplemented with 1% palm oil (Song et al., 2009). Ethyl EPA supplemented rats also have reduced depressive behavior in the open field test and improved scores in the Morris water maze (Song et al., 2009). The BAFF (B cell activating factor belonging to the TNF family) transgenic mouse is a mouse model that presents as a model of auto-immune disease. This model has neuroinflammation, specifically microglia activation (Crupi et al., 2010). When compared to a n-3 PUFA deficient control, BAFF transgenic mice consuming a diet containing 1.54% n-3 PUFA (% of total fatty acids, combination of ALA, EPA and DHA) have improved neurogenesis and long term potentiation, and lower hippocampal CD68 protein concentrations (Crupi et al., 2012). Surgery is associated with cognitive decline (Mashour et al., 2014). Administering 100 ng of the SPM aspirin-triggered RvD1 to mice prior to tibia fracture stabilization increases and improves memory retention compared to mice receiving vehicle control. This protection against surgery-induced cognitive decline was accompanied with an increase in GFAP labeling in the hippocampus (Terrando et al., 2013). N-methyl-D-aspartate (NMDA)-induced excitotoxicity increases inflammatory markers in the brain, including GFAP (Rao et al., 2007). Fish oil supplemented and n-3 PUFA adequate diets appears to decrease NMDA-induced calcium-dependent cytosolic PLA2 activity compared to diets deficient in n-3 PUFA, despite not changing calcium-dependent cytosolic PLA2 protein level. Fish oil and n-3 PUFA adequate diets also did not modify NMDA-induced GFAP, IL-1β and secreted PLA2 increases in protein levels (Keleshian et al., 2014). In some instances, however, reducing inflammation with n-3 PUFA has been reported to worsen symptoms. In the G93A-SOD1 mouse, a model of amyotrophic lateral sclerosis, pre-symptomatic mice fed 343 mg/kg/d of n-3 PUFA for 6 weeks have lowered GFAP and microglial marker levels, but accelerated symptom progression and increased lipid peroxidation compared to mice on control diet (Yip et al., 2013).

3. Conclusion In animal models, n-3 PUFA are generally associated with protection against neuroinflammation, although with varying efficacy and consistency between disease models. Herein we have summarized the growing body of literature on the modulation of neuroinflammation by n-3 PUFA in animal models of stroke, spinal cord injury, aging, Alzheimer’s disease, Parkinson’s disease, LPS and IL-1β injections, diabetes, neuropathic pain, traumatic brain injury, depression, surgically induced cognitive decline, whole body irradiation, amyotrophic lateral sclerosis, NMDA-induced excitotoxicity and lupus. In some cases, such as stroke, n-3 PUFA consistently reduce inflammatory markers, whereas in other instances such as in spinal cord injury, the results are relatively mixed. The differences in results may be due to heterogeneity between studies. There are vast differences between the type of n-3 PUFA administered (e.g. ALA vs. EPA vs. DHA), the route of administration (i.v. vs. p.o. vs. i.p. vs. i.c.v. vs. i.t.), the dose (e.g. ng to mg), the duration of administration (acute bolus to 18 months), the

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inclusion of antioxidants, the inflammatory markers (microglial vs. astrocytic vs. cytokines) measured and the timing of measurement. Moreover, control diets used in the studies reviewed vary greatly in n-3 PUFA content, with some studies using an n-3 PUFA adequate diet while others use an n-3 PUFA deficient diet. Thus, it is often unclear whether the phenotype observed in the treatment group is related to supplementation or lack of apparent deficiency. Considering that the relationship between n-3 PUFA levels is likely not linear to their biological effects (Trepanier et al., 2012), it is difficult to compare studies that use different baselines to determine the efficacy of augmenting n-3 PUFA levels. As many studies measured only a single cellular marker in their experiments, it is important to note that differentiation between various immune cell types is often difficult or impossible based on a single marker. For example, microglia and peripheral macrophages share multiple known surface markers, and only techniques that can compare the origin of the cells or the relative expression of various surface markers, such as flow cytometry, are reliable for identification (Carson et al., 2006b; Yamasaki et al., 2014). In addition, neutrophils have also been shown to express CD68 and CD11b on occasion, while macrophages can express the common neutrophil marker MPO, highlighting the need for multiple methods of identification (Matsumoto et al., 2007). It is also important to take into consideration that most studies evaluated the expression of neuroinflammatory marker(s) at a single time point. Different cellular markers and cytokines, however, have different time courses of expression (Loane and Byrnes, 2010; Schwartz and Baruch, 2014). Evaluating only single time points may result in false negatives, and limits any conclusion to be made on the resolution of neuroinflammation. Due to the small number of null studies reported in this review, combined with the multiple variables mentioned above, it is difficult to define therapeutic dose and duration of administration when comparing null studies with studies that found a positive or negative effect of n-3 PUFA. Considering this, there does not appear to be a definite therapeutic acute dose across all studies. A similar issue arises with duration of n-3 PUFA treatment, which does not appear to be associated with efficacy. It may be possible to suggest, however, that DHA is more potent than EPA. Out of 3 studies that evaluated the anti-inflammatory effects of EPA alone (Black et al., 1984; Lim et al., 2010; Okabe et al., 2011), only one reported anti-inflammatory properties of EPA (Okabe et al., 2011). Due to small number of studies and differences in models, more studies are needed to confirm the higher potency of DHA. From the data presented in this review, it is also hard to conclude if n-3 PUFA always act directly on neuroinflammatory pathways. It is possible that n-3 PUFA reduce the injury directly, such as by decreasing infarct size or neuronal cell death, and attenuated the neuroinflammatory response that accompanies such injuries as a consequence. Studies infusing IL-1β and LPS, however, directly activate neuroinflammatory pathways with minimal injury. Consistent with the direct anti-inflammatory properties of n-3 PUFA observed in cell culture (Hjorth et al., 2013), n-3 PUFA reduced neuroinflammation in response to i.c.v. injection of both LPS and IL-1β, indicating that n-3 PUFA may have the ability to impact neuroinflammatory pathways separate from their modulation of non-inflammatory pathways. The mechanism by which n-3 PUFA convey their anti-inflammatory properties is not elucidated. One hypothesis is that enzymatic metabolism of n-3 PUFA to bioactive mediators is primarily responsible for the anti-inflammatory effect of increased tissue n-3 PUFA levels. As reported above, these bioactive lipid mediators are sufficient to reduce neuroinflammation in stroke, i.c. v. LPS, neuropathic pain models, and surgery-induced cognitive decline. Future studies evaluating the mechanism of n-3 PUFA in neuroinflammation are warranted.

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N-3 PUFA administration has been tested in multiple clinical trials for various neurological and psychiatric disorders which have yielded mixed results (Amminger et al., 2010; Freund-Levi et al., 2006; Mischoulon et al., 2015; Torkildsen et al., 2012). It is unknown, however, whether neuroinflammation was actually targeted and lowered in these trials. With the link between neuroinflammation and both neurological and psychiatric disorders (Heneka et al., 2015; Najjar et al., 2013), it would be important to correlate any reduction of neuroinflammation to symptoms. With the development of TSPO ligands, TSPO being a receptor highly expressed in activated microglia, for positron emission tomography imaging, neuroinflammation can now be imaged in vivo in humans (Suridjan et al., 2015). Since n-3 PUFA modulate microglia markers such as Iba1 as described above, future clinical studies in humans could image neuroinflammation following n-3 PUFA treatment and relate TSPO binding with any reduction in symptoms. Overall, this review summarizes the literature on n-3 PUFA and neuroinflammation. N-3 PUFA appear to target brain inflammation signaling in a variety of animal models. However, the mechanism by which n-3 PUFA are anti-neuroinflammatory or whether the neuroinflammatory effects observed are direct effects or secondary are yet to be determined.

Acknowledgment This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada, Canada and the Canadian Institutes of Health Research, Canada to RPB. MOT received a studentship from the Natural Sciences and Engineering Research Council of Canada and RPB holds a Canada Research Chair in Brain Lipid Metabolism.

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