title: Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke.
abstract: Acute AMPK activation exacerbates ischemic brain damage experimentally. Paradoxically, the clinical use of an AMPK activator metformin reduces the incidence of stroke. We investigated whether post-stroke chronic metformin treatment promotes functional recovery and tissue repair via an M2-polarization mechanism following experimental stroke. Mice were randomly divided to receive metformin or vehicle daily beginning at 24h after middle cerebral artery occlusion (MCAO). Neurological deficits were monitored for 30days following MCAO. To characterize the polarization of the microglia and infiltrating macrophages, the expression of the M1 and M2 signature genes was analyzed with qPCR, ELISA and immunohistochemistry. Post-MCAO angiogenesis and neurogenesis were examined immunohistochemically. An in vitro angiogenesis model was employed to examine whether metformin promoted angiogenesis in a M2 polarization-dependent manner. Post-stroke chronic metformin treatment had no impact on acute infarction but enhanced cerebral AMPK activation, promoted functional recovery and skewed the microglia/macrophages toward an M2 phenotype following MCAO. Metformin also significantly increased angiogenesis and neurogenesis in the ischemic brain. Consistently, metformin-induced M2 polarization of BV2 microglial cells depended on AMPK activation in vitro. Furthermore, treatment of brain endothelial cells with conditioned media collected from metformin-polarized BV2 cells promoted angiogenesis in vitro. In conclusion, post-stroke chronic metformin treatment improved functional recovery following MCAO via AMPK-dependent M2 polarization. Modulation of microglia/macrophage polarization represents a novel therapeutic strategy for stroke.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, China; The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Shanwen
authors.initials: S
authors.lastname: Wei
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: jialijia8@sina.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: zhenxuechu@suda.edu.cn.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D020127:Recovery of Function; D015398:Signal Transduction; D020521:Stroke / Q000188:drug therapy*
chemical_list: D043925:Angiogenesis Inducing Agents; D018696:Neuroprotective Agents; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: Functional recovery; Metformin; Microglia/macrophages; Polarization; Stroke