Advertisement

European Journal of Nutrition

, Volume 57, Issue 5, pp 1781–1791 | Cite as

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

  • Yilong Dong
  • Min Xu
  • Allan V. Kalueff
  • Cai Song
Original Contribution

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Eicosapentaenoic acid IL-1β Inflammation Brain-derived neurotrophic factor Proinflammatory cytokine 

Abbreviations

AA

Arachidonic acid

AD

Alzheimer’s disease

APP

Amyloid precursor protein

BDNF

Brain-derived neurotrophic factor

cPLA2

Calcium-dependent phospholipase A2

DHA

Docosahexaenoic acid

DPA

Docosapentaenoic acid

EPA

Eicosapentaenoic acid

GC

Gas chromatography

GFAP

Glial fibrillary acidic protein

IL-1β

Interleukin-1β

LA

Linoleic acids

MAPK

Mitogen-activated protein kinase

p75NTR

p75 neurotrophin receptor

PUFAs

Polyunsaturated fatty acids

ROS

Reactive oxygen species

TNF-α

Tumor-necrosis factor-α

TrkB

Tyrosine receptor kinase B

Notes

Acknowledgements

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.

Author contribution

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.

References

  1. 1.
    Esiri MM (2007) The interplay between inflammation and neurodegeneration in CNS disease. J Neuroimmunol 184(1–2):4–16. doi: 10.1016/j.jneuroim.2006.11.013 CrossRefGoogle Scholar
  2. 2.
    Mrak RE, Griffin WST (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26(3):349–354. doi: 10.1016/jneurobiolaging.2004.05.010 CrossRefGoogle Scholar
  3. 3.
    Finch CE, Morgan TE (2007) Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a positionpaper. Curr Alzheimer Res 4(2):185–189CrossRefGoogle Scholar
  4. 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. 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
  6. 6.
    Song C, Zhang Y, Dong Y (2013) Acute and subacute IL-1β administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. J Neuroinflammation 10:59. doi: 10.1186/1742-2094-10-59 CrossRefGoogle Scholar
  7. 7.
    Min SK, Park JS, Luo L, Kwon YS, Lee HC, Shim HJ, Kim ID, Lee JK, Shin HS (2015) Assessment of C-phycocyanin effect on astrocytes-mediated neuroprotection against oxidative brain injury using 2D and 3D astrocyte tissue model. Sci Rep 5:14418. doi: 10.1038/srep14418 CrossRefGoogle Scholar
  8. 8.
    Lee J, Fukumoto H, Orne J, Klucken J, Raju S, Vanderburg CR, Irizarry MC, Hyman BT, Ingelsson M (2005) Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms. Exp Neurol 194(1):91–96. doi: 10.1016/j.expneurol.2005.01.026 CrossRefGoogle Scholar
  9. 9.
    Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, Bartels M, Buchkremer G, Schott K (2006) Stage dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm 113(9):1217–1224. doi: 10.1007/s00702-005-0397-y CrossRefGoogle Scholar
  10. 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
  11. 11.
    Jiang Y, Wei N, Lu T, Zhu J, Xu G, Liu X (2011) Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats. Neuroscience 172:398–405. doi: 10.1016/jneuroscience.2010.10.054 CrossRefGoogle Scholar
  12. 12.
    Al-Amin MM, Reza HM (2014) Neuroinflammation: contemporary anti-inflammatory treatment approaches. Neurosciences (Riyadh) 19(2):87–92Google Scholar
  13. 13.
    Song C, Li X, Leonard BE, Horrobin DF (2003) Effects of dietary n-3 or n-6 fatty acids on interleukin-1beta-induced anxiety, stress, and inflammatory responses in rats. J Lipid Res 44(10):1984–1991. doi: 10.1194/jlr.M300217-JLR200 CrossRefGoogle Scholar
  14. 14.
    Song C, Horrobin D (2004) Omega-3 fatty acid ethyl-eicosapentaenoate, but not soybean oil, attenuates memory impairment induced by central IL-1beta administration. J Lipid Res 45(6):1112–1121. doi: 10.1194/jlr.M300526-JLR200 CrossRefGoogle Scholar
  15. 15.
    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(5):954–963CrossRefGoogle Scholar
  16. 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
  17. 17.
    Russo GL (2009) Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol 77(6):937–946. doi: 10.1016/j.bcp.2008.10.020 CrossRefGoogle Scholar
  18. 18.
    Lone AM, Taskén K (2013) Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Front Immunol 4:130. doi: 10.3389/fimmu.2013.00130 CrossRefGoogle Scholar
  19. 19.
    Bernardo A, Minghetti L (2006) PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm 12(1):93–109CrossRefGoogle Scholar
  20. 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
  21. 21.
    Hashimoto M, Hossain S (2011) Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: beneficial effect of docosahexaenoic acid on cognitive decline in Alzheimer’s disease. Pharmacol Sci 116(2):150–162CrossRefGoogle Scholar
  22. 22.
    Horrobin DF (2002) A new category of psychotropic drugs: neuroactive lipids as exemplified by ethyl eicosapentaenoate (E-E). Prog Drug Res 59:171–199CrossRefGoogle Scholar
  23. 23.
    Peet M, Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 65(8):1051–1059CrossRefGoogle Scholar
  24. 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. 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. 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. 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
  28. 28.
    Qian L, Hong JS, Flood PM (2006) Role of microglia in inflammation-mediated degeneration of dopaminergic neurons: neuroprotective effect of interleukin 10. J Neural Transm Suppl 70:367–371CrossRefGoogle Scholar
  29. 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
  30. 30.
    Capsoni S, Brandi R, Arisi I, D’Onofrio M, Cattaneo A (2011) A dual mechanism linking NGF/proNGF imbalance and early inflammation to Alzheimer’s disease neurodegeneration in the AD11 anti-NGF mouse model. CNS Neurol Disord Drug Targets 10(5):635–647CrossRefGoogle Scholar
  31. 31.
    Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642. doi: 10.1146/annurev.biochem.72.121801.161629 CrossRefGoogle Scholar
  32. 32.
    Bibel M, Barde YA (2000) Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 14(23):2919–2937CrossRefGoogle Scholar
  33. 33.
    Mamidipudi V, Wooten MW (2002) Dual Role for p75NTR signaling in survival and cell death: can intracellular mediators provide and explanation? J Neurosci 68(4):373–384. doi: 10.1002/jnr.10244 Google Scholar
  34. 34.
    Madani S, Hichami A, Legrand A, Belleville J, Khan NA (2001) Implication of acyl chain of diacylglycerols in activation of different isoforms of protein kinase C. FASEB J 15(14):2595–2601. doi: 10.1096/fj.01-0753int CrossRefGoogle Scholar
  35. 35.
    Lee JG, Cho HY, Park SW, Seo MK, Kim YH (2010) Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 34(6):1001–1006. doi: 10.1016/j.pnpbp.2010.05.013 CrossRefGoogle Scholar
  36. 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
  37. 37.
    Tanikawa M, Lee HY, Watanabe K, Majewska M, Skarzynski DJ, Park SB, Lee DS, Park CK, Acosta TJ, Okuda K (2008) Regulation of prostaglandin biosynthesis by interleukin-1 in cultured bovine endometrial cells. J Endocrinol 199(3):425–434. doi: 10.1677/JOE-08-0237 CrossRefGoogle Scholar
  38. 38.
    Sanchez-Mejia RO,Mucke L (2010) Phospholipase A2 and arachidonic acid in Alzheimer’s disease. Biochim Biophys Acta. Biochim Biophys Acta 1801(8):784–790. doi: 10.1016/j.bbalip.2010.05.013 Google Scholar
  39. 39.
    Willis S, Samala R, Rosenberger TA, Borges K (2009) Eicosapentaenoic and docosahexaenoic acids are not anticonvulsant or neuroprotective in acute mouse seizure models. Epilepsia 50(1):138–142. doi: 10.1111/j.1528-1167.2008.01722.x CrossRefGoogle Scholar
  40. 40.
    Igarashi M, DeMar JC Jr, Ma K, Chang L, Bell JM, Rapoport SI (2007) Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is unaffected by dietary n-3 PUFA deprivation. J Lipid Res 48(5):1150–1158. doi: 10.1194/jlr.M600549-JLR200 CrossRefGoogle Scholar
  41. 41.
    Bourre JM, Dumont OS, Piciotti MJ, Pascal GA, Gurand GA (1992) Dietary alpha-linolenic acid deficiency in adult rats for 7 months does not alter brain docosahexaenoic acid content, in contrast to liver, heart and testes. Biochim Biophys Acta 1124(2):119–122CrossRefGoogle Scholar
  42. 42.
    Siegert E, Paul F, Rothe M, Weylandt KH (2017) The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice. BMC Neurosci 18(1):19. doi: 10.1186/s12868-016-0312-5 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yilong Dong
    • 1
    • 4
  • Min Xu
    • 4
  • Allan V. Kalueff
    • 2
    • 5
    • 6
  • Cai Song
    • 2
    • 3
  1. 1.School of MedicineYunnan UniversityKunmingChina
  2. 2.Research Institute for Marine Drugs and Nutrition, College of Food Science and TechnologyGuangdong Ocean UniversityZhanjiangChina
  3. 3.Department of Medical Research, Graduate Institute of Neural and Cognitive SciencesChina Medical University HospitalTaichungTaiwan
  4. 4.Department of Biomedical ScienceAVC, University of Prince Edward IslandCharlottetownCanada
  5. 5.Ural Federal UniversityEkaterinburgRussia
  6. 6.Institute of Translational BiomedicineSt Petersburg State UniversitySt PetersburgRussia

Personalised recommendations