humanin and Cerebral-Infarction

Oligodendrocytes are the predominant cell type in white matter and are highly vulnerable to ischemic injury. The role of oligodendrocyte dysfunction in ischemic brain injury is unknown. In this study, we used a 24-amino acid peptide S14G-Humanin (HNG) to examine oligodendrogenesis and neurological functional recovery in a hypoxic/ischemic (H/I) neonatal model. Intraperitoneal HNG pre-treatment decreased infarct volume following H/I injury. Delayed HNG treatment 24 h after H/I injury did not reduce infarct volume but did decrease neurological deficits and brain atrophy. Delayed HNG treatment did not attenuate axonal demyelination at 48 h after H/I injury. However, at 14 d after H/I injury, delayed HNG treatment increased axonal remyelination, the thickness of corpus callosum at the midline, the number of Olig2(+) /BrdU(+) cells, and levels of brain-derived neurotrophic factor (BDNF). Our results suggest that targeting oligodendrogenesis via delayed HNG treatment may represent a promising approach for the treatment of stroke.

Topics: Animals; Animals, Newborn; Atrophy; Axons; Brain-Derived Neurotrophic Factor; Cerebral Infarction; Disease Models, Animal; Hypoxia-Ischemia, Brain; Intracellular Signaling Peptides and Proteins; Neurogenesis; Oligodendroglia; Random Allocation; Rats; Rats, Sprague-Dawley; Recovery of Function

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.

Topics: Androstadienes; Animals; Benzylamines; Blotting, Western; Brain; Brain Ischemia; Cell Death; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebral Infarction; Glucose; Infarction, Middle Cerebral Artery; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins; Male; Mice; Neurons; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinoxalines; Reperfusion Injury; Signal Transduction; Wortmannin