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A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

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Abstract

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 h after 60 min of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment-facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

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Acknowledgments

This project was supported by the US Department of Veterans Affairs (VA) RR&D Merit Review RX000420, the US National Institutes of Health grants NS045048, NS091175 and NS095671, the American Heart Association grant 13SDG14570025, and the Chinese Natural Science Foundation grants 81529002, 81171149, 81371306, 81571285 and 81100978. J.C. is a recipient of the VA Senior Research Career Scientist Award. The authors are indebted to Pat Strickler for excellent administrative support.

Author Contributions

Y.S., X.H., Y.G., and J.C. designed the research. X.J., H.P., Z.W., and W.Z. performed the research. X.J. and Y.S. analyzed the data. X.J., H.P., D.H., J.C., and Y.S. wrote the manuscript. All authors reviewed and edited the manuscript.

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Authors and Affiliations

  1. State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China

    Xiaoyan Jiang, Xiaoming Hu, Wenting Zhang, Yanqin Gao & Jun Chen

  2. Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Xiaoyan Jiang, Hongjian Pu, Xiaoming Hu, Zhishuo Wei, Dandan Hong, Yanqin Gao, Jun Chen & Yejie Shi

  3. Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA

    Xiaoming Hu, Jun Chen & Yejie Shi

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  1. Xiaoyan Jiang
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Correspondence to Jun Chen or Yejie Shi.

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All animal procedures were approved by the University of Pittsburgh Institutional Animal Care and Use Committee and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Xiaoyan Jiang and Hongjian Pu contributed equally to this work

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Jiang, X., Pu, H., Hu, X. et al. A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia. Transl. Stroke Res. 7, 548–561 (2016). https://doi.org/10.1007/s12975-016-0502-6

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