title: Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke.
abstract: Prophylactic dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs) has been shown to remarkably ameliorate ischemic brain injury. However, the therapeutic efficacy of n-3 PUFA administration post-stroke, especially its impact on neurovascular remodeling and long-term neurological recovery, has not been fully characterized thus far. In this study, we investigated the effect of n-3 PUFA supplementation, as well as in combination with docosahexaenoic acid (DHA) injections, on long-term stroke outcomes. Mice were subjected to transient middle cerebral artery occlusion (MCAO) before randomly assigned to four groups to receive the following: (1) low dose of n-3 PUFAs as the vehicle control, (2) intraperitoneal DHA injections, (3) n-3 PUFA dietary supplement, or (4) combined treatment of (2) and (3). Neurological deficits and brain atrophy, neurogenesis, angiogenesis, and glial scar formation were assessed up to 28 days after MCAO. Results revealed that groups 2 and 3 showed only marginal reduction in post-stroke tissue loss and attenuation of cognitive deficits. Interestingly, group 4 exhibited significantly reduced tissue atrophy and improved cognitive functions compared to groups 2 and 3 with just a single treatment. Mechanistically, the combined treatment promoted post-stroke neurogenesis and angiogenesis, as well as reduced glial scar formation, all of which significantly correlated with the improved spatial memory in the Morris water maze. These results demonstrate an effective therapeutic regimen to enhance neurovascular restoration and long-term cognitive recovery in the mouse model of MCAO. Combined post-stroke DHA treatment and n-3 PUFA dietary supplementation thus may be a potential clinically translatable therapy for stroke or related brain disorders.
authors: Geriatric Research, Educational, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors: Hongjian
authors: H
authors: Pu
authors: 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: Xiaoyan
authors: X
authors: Jiang
authors: Geriatric Research, Educational, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA.|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: Xiaoming
authors: X
authors: Hu
authors: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors: Jinchao
authors: J
authors: Xia
authors: Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors: Dandan
authors: D
authors: Hong
authors: State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
authors: Wenting
authors: W
authors: Zhang
authors: 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: Yanqin
authors: Y
authors: Gao
authors: Geriatric Research, Educational, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA. chenj2@upmc.edu.|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.
authors: Jun
authors: J
authors: Chen
authors: Geriatric Research, Educational, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15261, USA. shiy3@upmc.edu.|Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. shiy3@upmc.edu.
authors: Yejie
authors: Y
authors: Shi
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D015525:Fatty Acids, Omega-3; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000628:therapy*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000178:diet therapy / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
chemical_list: D015525:Fatty Acids, Omega-3; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D004281:Docosahexaenoic Acids; D010751:Phosphopyruvate Hydratase
keywords: Angiogenesis; Cognitive function; Glial scar; Hippocampus; Neurogenesis