Dietary eicosapentaenoic acid normalizes hippocampal omega-3 and 6 polyunsaturated fatty acid profile, attenuates glial activation and regulates BDNF function in a rodent model of neuroinflammation induced by central interleukin-1β administration
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Interleukin (IL)-1β can activate glial cells to trigger neuroinflammation and neurodegeneration. Lower omega (n)-3 polyunsaturated fatty acids (PUFAs) and lower n-3/n-6 PUFA ratios occur in the brain of patients with Alzheimer’s disease (AD). We have previously reported that an n-3 PUFA, eicosapentaenoic acid (EPA), can improve memory and attenuate neurodegeneration-like changes in animal models of AD. However, whether and how EPA modulates glial cell activity and functions remains unclear. The aim of this study was to test the hypothesis that EPA may attenuate neuroinflammation by inhibiting microglial activation and microglia-produced proinflammatory cytokines, and by enhancing the expression of astrocytes-produced neurotrophins and their receptors.
Male Long-Evans rats were fed either palm oil supplemented diet or EPA supplemented diet for 42 days. On day 36 of diet feeding, rats received an intracerebroventricular injection of IL-1β or saline for 7 days. The glial activation, the expression of amyloid precursor protein (APP), calcium-dependent phospholipase (cPL) A2, brain-derived neurotrophic factor (BDNF) and its receptor, and PUFA profile in the hippocampus were analyzed.
IL-1β elevated biomarkers of microglial CD11b and astrocyte GFAP expression, increased the expression of APP, tumor-necrosis factor (TNF)-α, but reduced BDNF and its receptor (TrKB). IL-1β also lowered n-3 EPA and docosapentaenoic acid concentrations but increased n-6 PUFAs and cPLA2 activity in the hippocampus. EPA supplement normalized the n-3 and n-6 PUFA profiles and cPLA2 levels, inhibited glial activation, reduced APP and TNF-α expression, as well as up-regulated BDNF and TrKB.
Supplementation with EPA appear to have potential effects on improving glial over-activation, n3/n6 imbalance and BDNF down-regulation, which contribute to anti-inflammatory and may provide beneficial effects on inflammation-associated disease such as AD.
KeywordsEicosapentaenoic acid IL-1β Inflammation Brain-derived neurotrophic factor Proinflammatory cytokine
Amyloid precursor protein
Brain-derived neurotrophic factor
Calcium-dependent phospholipase A2
Glial fibrillary acidic protein
Mitogen-activated protein kinase
p75 neurotrophin receptor
Polyunsaturated fatty acids
Reactive oxygen species
Tyrosine receptor kinase B
This work was supported by grants from the National Natural Science Funds of China to CS (81171118) and to YLD (81360179), the Education Department of Guangdong Provincial grant to CS (Q14183, Q14175), as well as by Famous Oversea Professor program of Ministry of Education of China to CS.
CS designed the experiments, analyzed the data, wrote and edited the manuscript. DYL performed the experiment, analyzed the data and drafted the manuscript. XM analyzed FA profile by GC and discussed the data, AK discussed the data and edited the manuscript. All authors have reviewed and approved the final version of the manuscript. Technical assistances provided by Dr. Azoy Kundu, Ms. Qinjia Meng and Ms. Yuyu Li are appreciated.
Conflict of interest
All authors declared no conflicts of interest. The study was partially funded by Amarine Neuroscience Ltd. (UK), a manufacturer of CNS drugs based in fatty acids. The funder had no involvement in guiding this study, interpreting its results, discussing its findings and writing the manuscript, and making the decision about the submission and publication.
- 4.Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405. doi: 10.1016/S1474-4422(15)70016-5 CrossRefGoogle Scholar
- 5.Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM (2011) Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J Immunol 187(12):6539–6549. doi: 10.4049/jimmunol.1100620 CrossRefGoogle Scholar
- 10.Bovolenta R, Zucchini S, Paradiso B, Rodi D, Merigo F, Navarro Mora G, Osculati F, Berto E, Marconi P, Marzola A, Fabene PF, Simonato M (2010) Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures. J Neuroinflammation 7:81. doi: 10.1186/1742-2094-7-81 CrossRefGoogle Scholar
- 12.Al-Amin MM, Reza HM (2014) Neuroinflammation: contemporary anti-inflammatory treatment approaches. Neurosciences (Riyadh) 19(2):87–92Google Scholar
- 16.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(4):217–234. doi: 10.1054/plef.1999.0037 CrossRefGoogle Scholar
- 20.Fernández-Fernández L, Comes G, Bolea I, Valente T, Ruiz J, Murtra P, Ramirez B, Anglés N, Reguant J, Morelló JR, Boada M, Hidalgo J, Escorihuela RM, Unzeta M (2012) LMN diet, rich in polyphenols and polyunsaturated fatty acids, improves mouse cognitive decline associated with aging and Alzheimer’s disease. Behav Brain Res 228:261–271. doi: 10.1016/j.bbr.2011.11.014 CrossRefGoogle Scholar
- 24.Taepavarapruk P, Song C (2010) Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment. J Neurochem 112(4):1054–1064. doi: 10.1111/j.1471-4159.2009.06524.x CrossRefGoogle Scholar
- 25.Zhou WW, Lu S, Su YJ, Xue D, Yu XL, Wang SW, Zhang H, Xu PX, Xie XX, Liu RT (2014) Decreasing oxidative stress and neuroinflammation with a multifunctional peptide rescues memory deficits in mice with Alzheimer disease. Free Radic Biol Med 74:50–63. doi: 10.1016/j.freeradbiomed.2014.06.013 CrossRefGoogle Scholar
- 26.Meng Q, Luchtman DW, El Bahh B, Zidichouski JA, Yang J, Song C (2010) Ethyl-eicosapentaenoate modulates changes in neurochemistry and brain lipids induced by parkinsonian neurotoxin 1-methyl-4-phenylpyridinium in mouse brain slices. Eur J Pharmacol 649(1–3):127–134. doi: 10.1016/j.ejphar.2010.09.046 CrossRefGoogle Scholar
- 27.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(3):736–744. doi: 10.1038/sj.npp.1301117 CrossRefGoogle Scholar
- 29.Colombo E, Cordiglieri C, Melli G, Newcombe J, Krumbholz M, Parada LF, Medico E, Hohlfeld R, Meinl E, Farina C (2012) Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. J Exp Med 209(3):521–535. doi: 10.1084/jem.20110698 CrossRefGoogle Scholar
- 36.Parazzoli S, Harmon JS, Vallerie SN, Zhang T, Zhou H, Robertson RP (2012) Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1β-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets. J Biol Chem 287(38):32246–32253. doi: 10.1074/jbc.M112.364612 CrossRefGoogle Scholar