title: Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion.
abstract: BACKGROUND
  Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.
  
  
  METHODS
  Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.
  
  
  RESULTS
  Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.
  
  
  CONCLUSIONS
  Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.
authors.forename: Yanqun
authors.initials: Y
authors.lastname: Liu
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tang
authors.forename: Yaning
authors.initials: Y
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Gu
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. yongting.wang@gmail.com.
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D020520:Brain Infarction / Q000188:drug therapy; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000172:deficiency; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000860:Hypoxia / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D018799:Intercellular Adhesion Molecule-1; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose