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Ghrelin Inhibits Apoptosis in Hypothalamic Neuronal Cells during Oxygen-Glucose Deprivation

Department of Pharmacology (H.C., E.K., S.S., S.J., D.L., S.P.), Kyunghee University School of Medicine and Institute for Basic Medical Sciences, and Department of Herbal Pharmacology (D.H.L., H.K.), College of Oriental Medicine, Kyunghee University, Seoul 130-701, Korea

Address all correspondence and requests for reprints to: Seungjoon Park, M.D., Ph.D., Department of Pharmacology, Kyunghee University School of Medicine, 1 Hoiki-dong, Dongdaemun-ku, Seoul 130-701, Korea. E-mail: sjpark{at}khu.ac.kr.

Ghrelin is an endogenous ligand for the GH secretagogue receptor, produced and secreted mainly from the stomach. Ghrelin stimulates GH release and induces positive energy balances. Previous studies have reported that ghrelin inhibits apoptosis in several cell types, but its antiapoptotic effect in neuronal cells is unknown. Therefore, we investigated the role of ghrelin in ischemic neuronal injury using primary hypothalamic neurons exposed to oxygen-glucose deprivation (OGD). Here we report that treatment of hypothalamic neurons with ghrelin inhibited OGD-induced cell death and apoptosis. Exposure of neurons to ghrelin caused rapid activation of ERK1/2. Ghrelin-induced activation of ERK1/2 and the antiapoptotic effect of ghrelin were blocked by chemical inhibition of MAPK, phosphatidylinositol 3 kinase, protein kinase C, and protein kinase A. Ghrelin attenuated OGD-induced activation of c-Jun NH2-terminal kinase and p-38 but not ERK1/2. We also investigated ghrelin regulation of apoptosis at the mitochondrial level. Ghrelin protected cells from OGD insult by inhibiting reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, ghrelin-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Finally, in vivo administration of ghrelin significantly reduced infarct volume in an animal model of ischemia. Our data indicate that ghrelin may act as a survival factor that preserves mitochondrial integrity and inhibits apoptotic pathways.

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