title: Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway.
abstract: Humanin (HN) is an anti-apoptotic peptide that suppresses neuronal cell death induced by Alzheimer's disease, prion protein fragments, and serum deprivation. Recently, we demonstrated that Gly14-HN (HNG), a variant of HN in which the 14th amino acid serine is replaced with glycine, can decrease apoptotic neuronal death and reduce infarct volume in a focal cerebral ischemia/reperfusion mouse model. In this study, we postulate that the mechanism of HNG's neuroprotective effect is mediated by the PI3K/Akt pathway. Oxygen-glucose deprivation (OGD) was performed in cultured mouse primary cortical neurons for 60 min. The effect of HNG and PI3K/Akt inhibitors on OGD-induced cell death was examined at 24 h after reperfusion. HNG increased cell viability after OGD in primary cortical neurons, whereas the PI3K/Akt inhibitors wortmannin and Akti-1/2 attenuated the protective effect of HNG. HNG rapidly increased Akt phosphorylation, an effect that was inhibited by wortmannin and Akti-1/2. Mouse brains were injected intraventricularly with HNG before being subjected to middle cerebral artery occlusion (MCAO). HNG treatment significantly elevated p-Akt levels after cerebral I/R injury and decreased infarct volume. The protective effect of HNG on infarct size was attenuated by wortmannin and Akti-1/2. Taken as a whole, these results suggest that PI3K/Akt activation mediates HNG's protective effect against hypoxia/ischemia reperfusion injury.
authors.affiliation: Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
authors.forename: Chu Chang
authors.initials: CC
authors.lastname: Chua
authors.forename: Jinping
authors.initials: J
authors.lastname: Gao
authors.forename: Kao-Wei
authors.initials: KW
authors.lastname: Chua
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Hamdy
authors.forename: Balvin H L
authors.initials: BH
authors.lastname: Chua
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
chemical_list: C501521:Akt-I-1,2 compound; D000730:Androstadienes; D001596:Benzylamines; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; C427211:humanin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D000077191:Wortmannin