title: Ghrelin gene products rescue cultured adult rat hippocampal neural stem cells from high glucose insult.
abstract: Adult hippocampal neurogenesis is decreased in type 2 diabetes, and this impairment appears to be important in cognitive dysfunction. Previous studies suggest that ghrelin gene products (acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (OB)) promote neurogenesis. Therefore, we hypothesize that ghrelin gene products may reduce the harmful effects of high glucose (HG) on hippocampal neural stem cells (NSCs). The aim of this study was to investigate the role of these peptides on the survival of cultured hippocampal NSCs exposed to HG insult. Treatment of hippocampal NSCs with AG, UAG or OB inhibited HG-induced cell death and apoptosis. Exposure of cells to the growth hormone secretagogue receptor 1a antagonist abolished the protective effects of AG against HG toxicity, whereas those of UAG or OB were preserved. All three peptides attenuated HG-induced decrease in BrdU-labeled and phosphohistone-H3-labeled cells. We also investigated the effects of ghrelin gene products on the regulation of apoptosis at the mitochondrial level. AG, UAG or OB rescued hippocampal NSCs from HG insult by inhibiting intracellular and mitochondrial reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, cells treated with ghrelin gene products showed an increased Bcl-2 and decreased Bax levels, thereby increasing the Bcl-2/Bax ratio, inhibiting cytochrome c release and preventing caspase-3 activation. Finally, AG-, UAG- or OB-mediated protection was dependent on the activities of adenosine monophosphate-activated protein kinase/uncoupling protein 2 pathway. Our data indicate that ghrelin gene products may act as survival factors that preserve mitochondrial function and inhibit oxidative stress-induced apoptosis.
authors.affiliation: Department of Biomedical ScienceGraduate School, Kyung Hee University, Seoul, Korea.
authors.forename: Sehee
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biomedical ScienceGraduate School, Kyung Hee University, Seoul, Korea.
authors.forename: Chanyang
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science InstituteSchool of Medicine, Kyung Hee University, Seoul, Korea sjpark@khu.ac.kr.
authors.forename: Seungjoon
authors.initials: S
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D054439:Ghrelin / Q000235:genetics / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053148:Caspase 3; D005947:Glucose
keywords: apoptosis; ghrelin gene products; high glucose; hippocampus; progenitor