HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0160v1 198/3/511    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chung, H. Articles by Park, S. Search for Related Content PubMed PubMed Citation Articles by Chung, H. Articles by Park, S.

H Chung, Pharmacology, Kyunghee University School of Medicine, Seoul, Korea, Republic of
S Seo, Pharmacology, Kyunghee University School of Medicine, Seoul, Korea, Republic of
M Moon, Pharmacology, Kyunghee University School of Medicine, Seoul, Korea, Republic of
S Park, Pharmacology, Kyunghee University School of Medicine, Seoul, 130-701, Korea, Republic of

Correspondence: Seungjoon Park, Email: sjpark{at}khu.ac.kr

Abstract

Only acylated ghrelin (AG) binds GH secretagogue 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-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 phposphorylation of ERK1/2, 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 contributes to the anti-apoptotic effects of ghrelin.