title: A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia.
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.
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China. chenj2@upmc.edu.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. chenj2@upmc.edu.|Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA. chenj2@upmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. shiy3@upmc.edu.|Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA. shiy3@upmc.edu.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003337:Corpus Callosum / Q000473:pathology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000627:therapeutic use; D015118:Eicosapentaenoic Acid / Q000494:pharmacology* / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D056784:Leukoencephalopathies / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D020521:Stroke / Q000150:complications; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; C499047:Mbp protein, mouse; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid
keywords: Corpus callosum; Microglial polarization; Myelin; Oligodendrogenesis