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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.
AuthorsXingshun Xu, Chu Chang Chua, Jinping Gao, Kao-Wei Chua, Hong Wang, Ronald C Hamdy, Balvin H L Chua
JournalBrain research (Brain Res) Vol. 1227 Pg. 12-8 (Aug 28 2008) ISSN: 0006-8993 [Print] Netherlands
PMID18590709 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Akt-I-1,2 compound
  • Androstadienes
  • Benzylamines
  • Intracellular Signaling Peptides and Proteins
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Quinoxalines
  • humanin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose
  • Wortmannin
Topics
  • Androstadienes (pharmacology)
  • Animals
  • Benzylamines (pharmacology)
  • Blotting, Western
  • Brain (drug effects, metabolism, pathology)
  • Brain Ischemia (complications)
  • Cell Death (drug effects)
  • Cell Hypoxia (physiology)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Cerebral Infarction (etiology, physiopathology, prevention & control)
  • Glucose (metabolism, pharmacology)
  • Infarction, Middle Cerebral Artery (complications, metabolism, pathology)
  • Injections, Intraventricular
  • Intracellular Signaling Peptides and Proteins (administration & dosage, therapeutic use)
  • Male
  • Mice
  • Neurons (drug effects, metabolism, pathology)
  • Neuroprotective Agents (administration & dosage, therapeutic use)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (pharmacology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Quinoxalines (pharmacology)
  • Reperfusion Injury (etiology, physiopathology, prevention & control)
  • Signal Transduction (drug effects)
  • Wortmannin

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