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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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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.

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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

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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.

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Authors and Affiliations

  1. School of Medicine, Yunnan University, Kunming, Yunnan, China

    Yilong Dong

  2. Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China

    Allan V. Kalueff & Cai Song

  3. Department of Medical Research, Graduate Institute of Neural and Cognitive Sciences, China Medical University Hospital, Taichung, Taiwan

    Cai Song

  4. Department of Biomedical Science, AVC, University of Prince Edward Island, Charlottetown, Canada

    Yilong Dong & Min Xu

  5. Ural Federal University, Ekaterinburg, Russia

    Allan V. Kalueff

  6. Institute of Translational Biomedicine, St Petersburg State University, St Petersburg, Russia

    Allan V. Kalueff

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  1. Yilong Dong
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  2. Min Xu
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  4. Cai Song
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Correspondence to Cai Song.

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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.

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Dong, Y., Xu, M., Kalueff, A.V. et al. 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. Eur J Nutr 57, 1781–1791 (2018). https://doi.org/10.1007/s00394-017-1462-7

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