title: Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats.
abstract: Although Metformin, a first-line antidiabetic drug, can ameliorate ischemia/reperfusion (I/R) induced brain damage, but how metformin benefits injured hippocampus and the mechanisms are still largely unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of metformin against ischemic brain damage induced by cerebral I/R and to explore whether the Akt-mediated down-regulation of the phosphorylation of JNK3 signaling pathway contributed to the protection provided by metformin. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of metformin on anxiety-like behavioral and cognitive impairment after I/R. Cresyl Violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of Akt1, JNK3, c-Jun and the expression of cleaved caspase-3. Through ischemia/reperfusion (I/R) rat model, we found that metformin could attenuate the deficits of hippocampal related behaviors and inhibit cell apoptosis. The western blot data showed that metformin could promote the activation of Akt1 and reduce the phosphorylation of JNK3 and c-Jun as well as elevation of cleaved caspase-3 in I/R brains. PI3K inhibitor reversed all the protective effects, further indicating that metformin protect hippocampus from ischemic damage through PI3K/Akt1/JNK3/c-Jun signaling pathway.
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China.
authors.forename: Xu-Hua
authors.initials: XH
authors.lastname: Ge
authors.affiliation: Department of pediatrics, Soochow University Affiliated Children's Hospital, Soochow University, Suzhou 215003, China.
authors.forename: Guo-Ji
authors.initials: GJ
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
authors.forename: De-Qin
authors.initials: DQ
authors.lastname: Geng
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China.
authors.forename: Han-Zhi
authors.initials: HZ
authors.lastname: Zhang
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China.
authors.forename: Juan-Mei
authors.initials: JM
authors.lastname: He
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China.
authors.forename: Ai-Zhen
authors.initials: AZ
authors.lastname: Guo
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Ma
authors.affiliation: Department of General Medicine, Yangpu Hospital of Tongji University, Department of General Practice of Tongji University, Shanghai 200090, China. Electronic address: tongjimge@163.com.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008687:Metformin / Q000494:pharmacology*; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053148:Caspase 3; D004791:Enzyme Inhibitors; D008687:Metformin; D048057:Mitogen-Activated Protein Kinase 10; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C494920:Akt1 protein, rat; C505410:Casp3 protein, rat
keywords: Akt; Caspase-3; Ischemia/reperfusion; JNK3; Metformin