title: Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy.
abstract: OBJECTIVE
  Recent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose-lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre-activation of AMPK-dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).
  
  
  METHODS
  Male Sprague-Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3-methyladenine, and were injected with a single dose of metformin (10 mg kg(-1), i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later.
  
  
  RESULTS
  A single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3-methyladenine.
  
  
  CONCLUSIONS
  These results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well-known hypoglycaemic drug, may have a practical clinical use for stroke prevention.
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.forename: Hui-Fu
authors.initials: HF
authors.lastname: Wang
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Qiao-Quan
authors.initials: QQ
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Shi
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000517:prevention & control*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; C025946:3-methyladenine; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000225:Adenine
keywords: AMPK; autophagy; metformin; neuroprotection; preconditioning; stroke