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

被引:243
作者
Jin, Qin [1 ,2 ]
Cheng, Jian [3 ,4 ]
Liu, Yang [1 ,2 ]
Wu, Jian [1 ,2 ]
Wang, Xiaoyu [1 ,2 ]
Wei, Shanwen [3 ]
Zhou, Xiaomei [3 ]
Qin, Zhenghong [1 ,2 ]
Jia, Jia [1 ,2 ]
Zhen, Xuechu [1 ,2 ]
机构
[1] Soochow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215021, Jiangsu, Peoples R China
[2] Soochow Univ, Coll Pharmaceut Sci, Suzhou 215021, Jiangsu, Peoples R China
[3] Soochow Univ, Inst Neurosci, Suzhou 215021, Jiangsu, Peoples R China
[4] Soochow Univ, Affiliated Hosp 2, Suzhou 215021, Jiangsu, Peoples R China
基金
美国国家科学基金会;
关键词
Microglia/macrophages; Polarization; Metformin; Functional recovery; Stroke; FOCAL CEREBRAL-ISCHEMIA; PROTEIN-KINASE; ADENOSINE-MONOPHOSPHATE; SPINAL-CORD; POLARIZATION; BRAIN; CELLS; INFLAMMATION; INHIBITION; MICROGLIA;
D O I
10.1016/j.bbi.2014.03.003
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
071005 [微生物学]; 100108 [医学免疫学];
摘要
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 24 h after middle cerebral artery occlusion (MCAO). Neurological deficits were monitored for 30 days 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. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:131 / 142
页数:12
相关论文
共 36 条
[1]
[Anonymous], LANCET
[2]
Repertoire of microglial and macrophage responses after spinal cord injury [J].
David, Samuel ;
Kroner, Antje .
NATURE REVIEWS NEUROSCIENCE, 2011, 12 (07) :388-399
[3]
Inflammation is detrimental for neurogenesis in adult brain [J].
Ekdahl, CT ;
Claasen, JH ;
Bonde, S ;
Kokaia, Z ;
Lindvall, O .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (23) :13632-13637
[4]
Microglial Cells Contribute to Endogenous Brain Defenses after Acute Neonatal Focal Stroke [J].
Faustino, Joel V. ;
Wang, Xia ;
Johnson, Cali E. ;
Klibanov, Alexander ;
Derugin, Nikita ;
Wendland, Michael F. ;
Vexler, Zinaida S. .
JOURNAL OF NEUROSCIENCE, 2011, 31 (36) :12992-13001
[5]
AMP-activated protein kinase-an energy sensor that regulates all aspects of cell function [J].
Hardie, D. Grahame .
GENES & DEVELOPMENT, 2011, 25 (18) :1895-1908
[6]
Plenary Lecture Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism [J].
Hardie, D. Grahame .
PROCEEDINGS OF THE NUTRITION SOCIETY, 2011, 70 (01) :92-99
[7]
Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia [J].
Hu, Li-Fang ;
Wong, Peter T. -H. ;
Moore, Philip K. ;
Bian, Jin-Song .
JOURNAL OF NEUROCHEMISTRY, 2007, 100 (04) :1121-1128
[8]
Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia [J].
Hu, Xiaoming ;
Li, Peiying ;
Guo, Yanling ;
Wang, Haiying ;
Leak, Rehana K. ;
Chen, Songela ;
Gao, Yanqin ;
Chen, Jun .
STROKE, 2012, 43 (11) :3063-U474
[9]
Oligogenesis and Oligodendrocyte Progenitor Maturation Vary in Different Brain Regions and Partially Correlate with Local Angiogenesis after Ischemic Stroke [J].
Jiang, Lidan ;
Shen, Fanxia ;
Degos, Vincent ;
Schonemann, Marcus ;
Pleasure, Samuel J. ;
Mellon, Synthia H. ;
Young, William L. ;
Su, Hua .
TRANSLATIONAL STROKE RESEARCH, 2011, 2 (03) :366-375
[10]
Metformin Attenuates Production of Nitric Oxide in Response to Lipopolysaccharide by Inhibiting MyD88-Independent Pathway [J].
Kato, Y. ;
Koide, N. ;
Komatsu, T. ;
Tumurkhuu, G. ;
Dagvadorj, J. ;
Kato, K. ;
Yokochi, T. .
HORMONE AND METABOLIC RESEARCH, 2010, 42 (09) :632-636