Abstract
Accumulating evidence suggests that the pathophysiology of depression might be associated with neuroinflammation, which could be attenuated by pharmacological treatment for depression. Omega-3 polyunsaturated fatty acids (PUFAs) are anti-inflammatory and exert antidepressant effects. The aim of this study was to identify the molecular mechanisms through which docosahexaenoic acid (DHA), the main omega-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. The results of this study showed that DHA reduced expressions of tumor necrosis factor-α, interleukin-6, nitric oxide synthase, and cyclo-oxygenase-2, induced by interferon-γ, and induced upregulation of heme oxygenase-1 (HO-1) in BV-2 microglia. The inhibitory effect of DHA on nitric oxide production was abolished by HO-1 inhibitor zinc protoporphyrin IX. In addition, DHA caused AKT and ERK activation in a time-dependent manner, and the DHA-induced HO-1 upregulation could be attenuated by PI-3 kinase/AKT and MEK/ERK inhibitors. DHA also increased IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation, whereas both nuclear factor-κB and IκB protease inhibitors could inhibit DHA-induced HO-1 expressions. The other major n-3 PUFA, eicosapentaenoic acid, showed similar effects of DHA on inflammation and HO-1 in repeated key experiments. In connecting with inflammation hypothesis of depression and clinical studies supporting the antidepressant effects of omega-3 PUFAs, this study provides a novel implication of the antidepressant mechanisms of DHA.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abraham NG, Kappas A (2008). Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60: 79–127.
Bal-Price A, Brown GC (2001). Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21: 6480–6491.
Bazan NG (2006). Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 29: 263–271.
Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990). Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27: 229–237.
Block ML, Zecca L, Hong JS (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8: 57–69.
Brand A, Bauer NG, Hallott A, Goldbaum O, Ghebremeskel K, Reifen R et al (2010). Membrane lipid modification by polyunsaturated fatty acids sensitizes oligodendroglial OLN-93 cells against oxidative stress and promotes upregulation of heme oxygenase-1 (HSP32). J Neurochem 113: 465–476.
Carlezon Jr WA, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF (2005). Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats. Biol Psychiatry 57: 343–350.
Charney DS, Manji HK (2004). Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004: re5.
Chen G, Zeng WZ, Yuan PX, Huang LD, Jiang YM, Zhao ZH et al (1999). The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem 72: 879–882.
Chen GG, Liu ZM, Vlantis AC, Tse GM, Leung BC, van Hasselt CA (2004). Heme oxygenase-1 protects against apoptosis induced by tumor necrosis factor-alpha and cycloheximide in papillary thyroid carcinoma cells. J Cell Biochem 92: 1246–1256.
Choi AM, Alam J (1996). Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15: 9–19.
Choi BM, Kim BR (2008). Upregulation of heme oxygenase-1 by brazilin via the phosphatidylinositol 3-kinase/Akt and ERK pathways and its protective effect against oxidative injury. Eur J Pharmacol 580: 12–18.
Crawford Jr GD, Le WD, Smith RG, Xie WJ, Stefani E, Appel SH (1992). A novel N18TG2 x mesencephalon cell hybrid expresses properties that suggest a dopaminergic cell line of substantia nigra origin. J Neurosci 12: 3392–3398.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9: 46–56.
De Smedt-Peyrusse V, Sargueil F, Moranis A, Harizi H, Mongrand S, Laye S (2008). Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization. J Neurochem 105: 296–307.
Duman RS, Malberg J, Nakagawa S, D’Sa C (2000). Neuronal plasticity and survival in mood disorders. Biol Psychiatry 48: 732–739.
Duman RS, Malberg J, Thome J (1999). Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 46: 1181–1191.
Ebert S, Weigelt K, Walczak Y, Drobnik W, Mauerer R, Hume DA et al (2009). Docosahexaenoic acid attenuates microglial activation and delays early retinal degeneration. J Neurochem 110: 1863–1875.
Farooqui AA, Ong WY, Horrocks LA (2006). Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev 58: 591–620.
Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M et al (2006). Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 67: 1954–1967.
Hanisch UK, Kettenmann H (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10: 1387–1394.
Hibbeln JR (1998). Fish consumption and major depression. Lancet 351: 1213.
Hill-Kapturczak N, Thamilselvan V, Liu F, Nick HS, Agarwal A (2001). Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol Renal Physiol 281: F851–F859.
Hirafuji M, Machida T, Tsunoda M, Miyamoto A, Minami M (2002). Docosahexaenoic acid potentiates interleukin-1beta induction of nitric oxide synthase through mechanism involving p44/42 MAPK activation in rat vascular smooth muscle cells. Br J Pharmacol 136: 613–619.
Horrobin DF, Bennett CN (1999). Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids 60: 217–234.
Huang SY, Yang HT, Chiu CC, Pariante CM, Su KP (2008). Omega-3 fatty acids on the forced-swimming test. J Psychiatr Res 42: 58–63.
Ida T, Hara M, Nakamura Y, Kozaki S, Tsunoda S, Ihara H (2008). Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide. Neurosci Lett 432: 232–236.
Juan SH, Cheng TH, Lin HC, Chu YL, Lee WS (2005). Mechanism of concentration-dependent induction of heme oxygenase-1 by resveratrol in human aortic smooth muscle cells. Biochem Pharmacol 69: 41–48.
Kawashima A, Harada T, Kami H, Yano T, Imada K, Mizuguchi K (2009). Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells. J Nutr Biochem 21: 268–277.
Kim KM, Pae HO, Zhung M, Ha HY, Ha YA, Chai KY et al (2008). Involvement of anti-inflammatory heme oxygenase-1 in the inhibitory effect of curcumin on the expression of pro-inflammatory inducible nitric oxide synthase in RAW264. 7 macrophages. Biomed Pharmacother 62: 630–636.
Komatsu W, Ishihara K, Murata M, Saito H, Shinohara K (2003). Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-gamma plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress. Free Radic Biol Med 34: 1006–1016.
Krishnan V, Nestler EJ (2008). The molecular neurobiology of depression. Nature 455: 894–902.
Lands WE (1992). Biochemistry and physiology of n-3 fatty acids. FASEB J 6: 2530–2536.
Lavrovsky Y, Schwartzman ML, Levere RD, Kappas A, Abraham NG (1994). Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci USA 91: 5987–5991.
Le WD, Xie WJ, Appel SH (1999). Protective role of heme oxygenase-1 in oxidative stress-induced neuronal injury. J Neurosci Res 56: 652–658.
Lee TS, Chau LY (2002). Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8: 240–246.
Li B, Zhang S, Zhang H, Nu W, Cai L, Hertz L et al (2008a). Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation. Psychopharmacology (Berl) 201: 443–458.
Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA (2008b). Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present. J Neurosci 28: 5321–5330.
Li W, Xia J, Sun GY (1999). Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate. J Interferon Cytokine Res 19: 121–127.
Lin CC, Chiang LL, Lin CH, Shih CH, Liao YT, Hsu MJ et al (2007). Transforming growth factor-beta1 stimulates heme oxygenase-1 expression via the PI3K/Akt and NF-kappaB pathways in human lung epithelial cells. Eur J Pharmacol 560: 101–109.
Lin PY, Huang SY, Su KP (2010). A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry (in press).
Lin PY, Su KP (2007). A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 68: 1056–1061.
Lu DY, Tang CH, Liou HC, Teng CM, Jeng KC, Kuo SC et al (2007). YC-1 attenuates LPS-induced proinflammatory responses and activation of nuclear factor-kappaB in microglia. Br J Pharmacol 151: 396–405.
Lu DY, Tang CH, Yeh WL, Wong KL, Lin CP, Chen YH et al (2009). SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. Eur J Pharmacol 613: 146–154.
Lu XH, Bradley RJ, Dwyer DS (2004). Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. Brain Res 1011: 58–68.
Lu XH, Dwyer DS (2005). Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 27: 43–64.
Lynch AM, Loane DJ, Minogue AM, Clarke RM, Kilroy D, Nally RE et al (2007). Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging 28: 845–855.
Maes M (2008). The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29: 287–291.
Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H (1996). Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Disord 38: 35–46.
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G et al (2009). The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24: 27–53.
Malaguarnera L, Imbesi R, Di RM, Scuto A, Castrogiovanni P, Messina A et al (2005). Action of prolactin, IFN-gamma, TNF-alpha and LPS on heme oxygenase-1 expression and VEGF release in human monocytes/macrophages. Int Immunopharmacol 5: 1458–1469.
Manji HK, Drevets WC, Charney DS (2001). The cellular neurobiology of depression. Nat Med 7: 541–547.
Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ (2003). A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 160: 996–998.
McNamara RK, Carlson SE (2006). Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fatty Acids 75: 329–349.
McNamara RK, Hahn CG, Jandacek R, Rider T, Tso P, Stanford KE et al (2007). Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol Psychiatry 62: 17–24.
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramauge M, Courtin F et al (2004). MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci 24: 207–216.
Miller AH, Maletic V, Raison CL (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65: 732–741.
Moon Y, Pestka JJ (2003). Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. J Nutr Biochem 14: 717–726.
Nakao A, Kaczorowski DJ, Zuckerbraun BS, Lei J, Faleo G, Deguchi K et al (2008). Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction. Biochem Biophys Res Commun 367: 674–679.
Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH (2006). Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 163: 1098–1100.
Ning W, Song R, Li C, Park E, Mohsenin A, Choi AM et al (2002). TGF-beta1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 283: L1094–L1102.
O’Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ (2009). Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration. Int J Neuropsychopharmacol 12: 687–699.
Pasparakis M (2009). Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9: 778–788.
Peet M, Horrobin DF (2002). A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 59: 913–919.
Peet M, Murphy B, Shay J, Horrobin D (1998). Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 43: 315–319.
Peet M, Stokes C (2005). Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 65: 1051–1059.
Raison CL, Capuron L, Miller AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27: 24–31.
Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y et al (2003). NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22: 3898–3909.
Saraiva M, O’Garra A (2010). The regulation of IL-10 production by immune cells. Nat Rev Immunol 10: 170–181.
Saw CL, Huang Y, Kong AN (2010). Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. Biochem Pharmacol 79: 421–430.
Seti H, Leikin-Frenkel A, Werner H (2009). Effects of omega-3 and omega-6 fatty acids on IGF-I receptor signalling in colorectal cancer cells. Arch Physiol Biochem 115: 127–136.
Shin TK, Kang MS, Lee HY, Seo MS, Kim SG, Kim CD et al (2009). Fluoxetine and sertraline attenuate postischemic brain injury in mice. Korean J Physiol Pharmacol 13: 257–263.
Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA (2005). Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 72: 211–218.
Song C, Leonard BE, Horrobin DF (2004a). Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats. Stress 7: 43–54.
Song C, Li X, Kang Z, Kadotomi Y (2007). Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion. Neuropsychopharmacology 32: 736–744.
Song C, Manku MS, Horrobin DF (2008). Long-chain polyunsaturated fatty acids modulate interleukin-1beta-induced changes in behavior, monoaminergic neurotransmitters, and brain inflammation in rats. J Nutr 138: 954–963.
Song C, Phillips AG, Leonard BE, Horrobin DF (2004b). Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. Mol Psychiatry 9: 630–638.
Su KP (2008). Mind-body interface: the role of n-3 fatty acids in psychoneuroimmunology, somatic presentation, and medical illness comorbidity of depression. Asia Pac J Clin Nutr 17 (Suppl 1): 151–157.
Su KP (2009). Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a ‘mind-body interface′? Neurosignals 17: 144–152.
Su KP, Huang SY, Chiu CC, Shen WW (2003). Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 13: 267–271.
Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC et al (2008). Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 69: 644–651.
Su KP, Huang SY, Peng CY, Lai HC, Huang CL, Chen YC et al (2010). Phospholipase A2 and Cyclooxygenase 2 Genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry 67: 550–557.
Su KP, Shen WW, Huang SY (2000). Effects of polyunsaturated fatty acids on psychiatric disorders. Am J Clin Nutr 72: 1241.
Tai YH, Tsai RY, Lin SL, Yeh CC, Wang JJ, Tao PL et al (2009). Amitriptyline suppresses neuroinflammation-dependent interleukin-10-p38 mitogen-activated protein kinase-heme oxygenase-1 signaling pathway in chronic morphine-infused rats. Anesthesiology 110: 1379–1389.
Tai YH, Wang YH, Wang JJ, Tao PL, Tung CS, Wong CS (2006). Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats. Pain 124: 77–86.
Tsoyi K, Kim HJ, Shin JS, Kim DH, Cho HJ, Lee SS et al (2008). HO-1 and JAK-2/STAT-1 signals are involved in preferential inhibition of iNOS over COX-2 gene expression by newly synthesized tetrahydroisoquinoline alkaloid, CKD712, in cells activated with lipopolysacchride. Cell Signal 20: 1839–1847.
Vareille M, Rannou F, Thelier N, Glasser AL, de ST, Martin C et al (2008). Heme oxygenase-1 is a critical regulator of nitric oxide production in enterohemorrhagic Escherichia coli-infected human enterocytes. J Immunol 180: 5720–5726.
Venna VR, Deplanque D, Allet C, Belarbi K, Hamdane M, Bordet R (2009). PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus. Psychoneuroendocrinology 34: 199–211.
Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, Wung BS (2006). Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci 78: 2889–2897.
Yavin E, Brand A, Green P (2002). Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress. Nutr Neurosci 5: 149–157.
Zhang M, Jin W, Zhou X, Yu J, Lee AJ, Sun SC (2009). Deregulation of Tpl2 and NF-kappaB signaling and induction of macrophage apoptosis by the anti-depressant drug lithium. Cell Signal 21: 559–566.
Acknowledgements
The work was supported by the following grants: NSC 98-2627-B-039-003, NSC 98-2627-B-039-005, and NSC 98-2628-B-039-020-MY3 from the National Science Council in Taiwan; CMU97-336, CMU97-340, and CMU97-341 from the China Medical University in Taiwan; and the NARSAD Young Investigator Award in the United States. We thank Dr WD Le at the Baylor College of Medicine, Texas, USA, for providing the MES 23.5 cell line and Mr MC Tseng for technical support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors report no biomedical financial interests or potential conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Rights and permissions
About this article
Cite this article
Lu, DY., Tsao, YY., Leung, YM. et al. Docosahexaenoic Acid Suppresses Neuroinflammatory Responses and Induces Heme Oxygenase-1 Expression in BV-2 Microglia: Implications of Antidepressant Effects for Omega-3 Fatty Acids. Neuropsychopharmacol 35, 2238–2248 (2010). https://doi.org/10.1038/npp.2010.98
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2010.98
Keywords
This article is cited by
-
Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients – a randomized controlled trial. (OxaNeuro)
BMC Cancer (2024)
-
Glucose increases proliferation and chemoresistance in chronic myeloid leukemia via decreasing antioxidant Properties of ω-3 polyunsaturated fatty acids in the presence of Iron
Molecular Biology Reports (2023)
-
The impact of maternal obesity on childhood neurodevelopment
Journal of Perinatology (2021)
-
A Walnut Diet in Combination with Enriched Environment Improves Cognitive Function and Affects Lipid Metabolites in Brain and Liver of Aged NMRI Mice
NeuroMolecular Medicine (2021)
-
Unveiling anti-oxidative and anti-inflammatory effects of docosahexaenoic acid and its lipid peroxidation product on lipopolysaccharide-stimulated BV-2 microglial cells
Journal of Neuroinflammation (2018)