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.
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Authors | Xingshun Xu, Chu Chang Chua, Jinping Gao, Kao-Wei Chua, Hong Wang, Ronald C Hamdy, Balvin H L Chua |
Journal | Brain research
(Brain Res)
Vol. 1227
Pg. 12-8
(Aug 28 2008)
ISSN: 0006-8993 [Print] Netherlands |
PMID | 18590709
(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.)
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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
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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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