title: Chronic Metformin Preconditioning Provides Neuroprotection via Suppression of NF-κB-Mediated Inflammatory Pathway in Rats with Permanent Cerebral Ischemia.
abstract: Accumulating evidence suggests that chronic metformin preconditioning offers potent neuroprotective effects against ischemic stroke. However, the underlying mechanisms remain largely unknown. In this study, we tested the hypothesis that chronic preconditioning with metformin conferred neuroprotection via suppression of nuclear factor kappa B (NF-κB)-mediated inflammatory pathway. Male Sprague-Dawley rats were treated with vehicle or metformin (50 mg/kg daily, i.p.) for 3 weeks and were subjected to permanent middle cerebral artery occlusion (pMCAO). At 24 h (acute phase) and 96 h (subacute phase) after pMCAO, infarct volume and neurological deficits were evaluated. Meanwhile, the activity of NF-κB and the levels of its downstream pro-inflammatory cytokines were detected at 24 h after pMCAO. Our results showed that chronic metformin preconditioning significantly reduced infarct volume and improved neurological deficits at 24 and 96 h after pMCAO. It also suppressed brain NF-κB activity, which was accompanied by a reduction of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and induced nitric oxide synthase in the peri-infarct regions at 24 h after pMCAO. Moreover, the microgliosis and astrocytosis induced by pMCAO were also ameliorated by chronic metformin preconditioning. Collectively, the present study provides the first evidence that suppression of NF-κB-mediated inflammatory pathway may represent one potential mechanism underlying the neuroprotection of chronic metformin preconditioning. In addition, our findings suggest that metformin, a first-line drug for glycemic control, has a practical clinical use for stroke prevention and treatment.
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.forename: Qiao-Quan
authors.initials: QQ
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.forename: Hui-Fu
authors.initials: HF
authors.lastname: Wang
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Ding
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
mesh_terms: D000208:Acute Disease; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000473:pathology
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D008687:Metformin