Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells
| Autor: | Sanghee Seo, Seungjoon Park, Minho Moon, Hyunju Chung |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Morpholines Endocrinology Diabetes and Metabolism Blotting Western Apoptosis Rats Sprague-Dawley Glycogen Synthase Kinase 3 Endocrinology GSK-3 Internal medicine medicine Animals Phosphorylation RNA Small Interfering Receptors Ghrelin Glycogen synthase Protein kinase B GSK3B Cells Cultured PI3K/AKT/mTOR pathway Cerebral Cortex Flavonoids Mitogen-Activated Protein Kinase 1 Neurons Glycogen Synthase Kinase 3 beta Mitogen-Activated Protein Kinase 3 biology Caspase 3 Reverse Transcriptase Polymerase Chain Reaction Kinase Immunohistochemistry Cell Hypoxia Ghrelin Rats Androstadienes Glucose Chromones biology.protein Wortmannin Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Endocrinology. 198:511-521 |
| ISSN: | 1479-6805 0022-0795 |
| DOI: | 10.1677/joe-08-0160 |
| Popis: | Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist d-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3β (GSK-3β). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of β-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and stabilization of β-catenin contribute to the anti-apoptotic effects of ghrelin. |
| Databáze: | OpenAIRE |
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