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, ca...

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Bibliographic Details
Published in:Brain research 2008-08, Vol.1227, p.12-18
Main Authors: Xu, Xingshun, Chua, Chu Chang, Gao, Jinping, Chua, Kao-Wei, Wang, Hong, Hamdy, Ronald C, Chua, Balvin H.L
Format: Article
Language:English
Subjects:
Androstadienes - pharmacology
Animals
Benzylamines - pharmacology
Biological and medical sciences
Blotting, Western
Brain - drug effects
Brain - metabolism
Brain - pathology
Brain Ischemia - complications
Cell Death - drug effects
Cell Hypoxia - physiology
Cell Survival - drug effects
Cells, Cultured
Cerebral Infarction - etiology
Cerebral Infarction - physiopathology
Cerebral Infarction - prevention & control
Cortical neuron
Glucose - metabolism
Glucose - pharmacology
Humanin
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - metabolism
Infarction, Middle Cerebral Artery - pathology
Injections, Intraventricular
Intracellular Signaling Peptides and Proteins - administration & dosage
Intracellular Signaling Peptides and Proteins - therapeutic use
Male
MCAO
Medical sciences
Mice
Neurology
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - therapeutic use
OGD
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation - drug effects
PI3K/Akt
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - metabolism
Quinoxalines - pharmacology
Reperfusion Injury - etiology
Reperfusion Injury - physiopathology
Reperfusion Injury - prevention & control
Signal Transduction - drug effects
Vascular diseases and vascular malformations of the nervous system
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Summary: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.
ISSN:0006-8993
1872-6240
DOI:10.1016/j.brainres.2008.06.018