title: Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1α pathway.
abstract: Here, we have investigated the effect of metformin pretreatment in the rat models of global cerebral ischemia. Cerebral ischemia which leads to brain dysfunction is one of the main causes of neurodegeneration and death worldwide. Metformin is used in clinical drug therapy protocols of diabetes. It is suggested that metformin protects cells under hypoxia and ischemia in non-neuronal contexts. Protective effects of metformin may be modulated via activating the AMP activated protein kinase (AMPK). Our results showed that induction of 30 min global cerebral I/R injury using 4-vesseles occlusion model led to significant cell death in the rat brain. Metformin pretreatment (200 mg kg/once/day, p.o., 2 weeks) attenuated apoptotic cell death and induced mitochondrial biogenesis proteins in the ischemic rats, analyzed using histological and Western blot assays. Besides, inhibition of AMPK by compound c showed that metformin resulted in apoptosis attenuation via AMPK activation. Interestingly, AMPK activation was also involved in the induction of mitochondrial biogenesis proteins using metformin, inhibition of AMPK by compound c reversed such effect, further supporting the role of AMPK upstream of mitochondrial biogenesis proteins. In summary, Metformin pretreatment is able to modulate mitochondrial biogenesis and apoptotic cell death pathways through AMPK activation in the context of global cerebral ischemia, conducting the outcome towards neuroprotection.
authors.affiliation: Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Ghorbangol
authors.initials: G
authors.lastname: Ashabi
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.forename: Leila
authors.initials: L
authors.lastname: Khalaj
authors.forename: Mahdi
authors.initials: M
authors.lastname: Goudarzvand
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Nasiri
mesh_terms: D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D063269:Mitochondrial Turnover / Q000187:drug effects; D051265:NF-E2-Related Factor 1 / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011292:Premedication; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D051265:NF-E2-Related Factor 1; D018696:Neuroprotective Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011720:Pyrazoles; D011743:Pyrimidines; C489030:Tfam protein, rat; D014157:Transcription Factors; C516138:dorsomorphin; D008687:Metformin; D000263:Adenylate Kinase