title: Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation.
abstract: 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.
authors.affiliation: Department of Pharmacology, Kyunghee University School of Medicine, Dongdaemun-ku, Seoul 130-701, Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Chung
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Sanghee
authors.initials: S
authors.lastname: Seo
authors.forename: Sunghee
authors.initials: S
authors.lastname: Ju
authors.forename: Dahm
authors.initials: D
authors.lastname: Lee
authors.forename: Hocheol
authors.initials: H
authors.lastname: Kim
authors.forename: Seungjoon
authors.initials: S
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D054439:Ghrelin; D005947:Glucose / Q000494:pharmacology; D007031:Hypothalamus / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology; D036361:Peptide Hormones / Q000494:pharmacology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D054440:Receptors, Ghrelin; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D054439:Ghrelin; D036361:Peptide Hormones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D005947:Glucose; D010100:Oxygen