title: Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway.
abstract: Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia. Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory. Materials and methods Rats were pretreated with metformin (200 mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured. Results Pretreatment with metformin (met) in the met + ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p < 0.001) and increased latency time compared with the I/R group (p < 0.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R + met group (p < 0.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p < 0.001) but increased that compared with the sham group (p < 0.001). The level of pro-BDNF decreased in the met + CC + I/R group compared with the met + I/R group (p < 0.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p < 0.001). Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK.
authors.affiliation: a Neurobiology Research Center, Shahid Beheshti University of Medical Sciences , Tehran , Iran ;
authors.forename: Negar
authors.initials: N
authors.lastname: Ghadernezhad
authors.affiliation: b Medical School, Alborz University of Medical Sciences , Alborz , Iran ;
authors.forename: Leila
authors.initials: L
authors.lastname: Khalaj
authors.affiliation: c Physiology Research Center and Department of Physiology, Faculty of Medicine , Iran University of Medical Sciences , Tehran , Iran ;
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Pazoki-Toroudi
authors.affiliation: d Neuroscience Research Center, Shahid Beheshti University of Medical Sciences , Tehran , Iran ;
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Mirmasoumi
authors.affiliation: e Physiology Research Center and Department of Physiology, School of Medicine , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran.
authors.forename: Ghorbangol
authors.initials: G
authors.lastname: Ashabi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D007858:Learning / Q000187:drug effects*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D016548:Prosencephalon / Q000098:blood supply*; D017208:Rats, Wistar; D011930:Reaction Time; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D008687:Metformin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases
keywords: AMPK; BDNF; compound C; global cerebral ischaemia; passive avoidance task