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.
Abstract. Intracerebroventricular (icv) administration of glucagon-like peptide-1 (GLP-1) inhibits food intake and induces c-fos expression in the hypothalamus. However, the effects of GLP-1 on hypothalamic neuronal activity or neuropeptide mRNA expression are unknown. In this study, we examined the effects of GLP-1 on fasting-induced changes in the expression of hypothalamic orexigenic and anorexigenic neuropeptide. Food intake was significantly inhibited after icv injection of GLP-1 in 48 h fasted rats. Hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNAs were significantly increased by fasting, whereas icv GLP-1 treatment significantly attenuated these fasting-induced increases. Both proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) mRNA levels were decreased by fasting, while GLP-1 treatment attenuated fasting-induced decreases in POMC and CART expression. We also determined the mRNA levels of AMP-activated kinase (AMPK) and found that fasting resulted in a significant stimulation of hypothalamic AMPKα2 mRNA. Fasting-induced increase in AMPKα2 mRNA was almost completely prevented by GLP-1 treatment. Analysis of phosphorylated AMPKα and acetyl CoA carboxylase showed similar results. Taken together, our observation suggests that the decreased food intake by GLP-1 is caused by preventing the fasting-induced increase in hypothalamic NPY and AgRP and the fasting-induced decrease in hypothalamic POMC and CART. Our results also suggest that the food intake lowering effect of GLP-1 is caused by reversing the fasting-induced increase in hypothalamic AMPK activity. Therefore we conclude that the anorectic effect of GLP-1 seems to be mediated by, at least in part, by the hypothalamus. GLUCAGON-LIKE peptide-1 (GLP-1) is synthesized from proglucagon-derived peptides in intestinal endocrine L cells and in selected neurons in the brain stem and hypothalamus [1]. The majority of circulating biologically active GLP-1 is found in the GLP-1-(7-36) amide form, with lesser amounts of the bioactive GLP-1-(7-37) form also detectable. The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. There has been extensive interest in understanding the role of GLP-1 in the control of satiety and food intake. Intracerebroventricular (icv) administration of GLP-1 or exendin-4 inhibited food intake and body weight in the rat [2][3][4]. These satietyrelated effects have also been observed in human studies with prandial subcutaneous injections of GLP-1 to obese subjects [5]. Blockade of central nervous system (CNS) GLP-1 action using icv infusion of GLP-1 receptor antagonist exendin (9-39) increased food intake and promoted weight gain in rats, suggesting the involvement of GLP-1 receptor in satiety [3]. Despite a large body of evidence demonstrates that GLP-1 is a potent inhibitor of food intake, the precise mechanism
Korean red ginseng (Panax ginseng C.A. Meyer) contains various pharmacologically active constituents including ginsenosides. Recently we found that red ginseng extract has a strong antioxidant activity and that pectinase‐mediated hydrolysis augments its radical‐scavenging activity. In addition, the content of compound‐K, a bioavailable and bioactive ginsenoside, was significantly increased in the hydrolyzed red ginseng extract compared to the non‐hydrolyzed extract. We further investigated neuroprotective and cognitive‐enhancing effects of the hydrolyzed red ginseng extract in vitro and in vivo. To induce oxidative stress‐induced neurotoxicity, mouse hippocampal HT22 cells and C57BL/6 mice were exposed to an excess glutamate and D‐galactose, respectively. For behavioral assessments, the passive avoidance, Y‐maze, and Morris water maze tasks were performed following treatment with the extracts or compound‐K. Our results from the in vitro and in vivo tests demonstrate that (1) red ginseng extract (containing compound‐K) protects neuronal cells from oxidative damage through the induction of Nrf2 and antioxidant enzymes, (2) the learning and memory impairments induced by oxidative stress were alleviated by treatment with the hydrolyzed red ginseng extract, (3) the hippocampi (particularly cell counts and nuclear arrangement) of the stressed mice was histologically pathologic, which was rarely observable from the hippocampi of the extract‐treated mice. Our findings suggest that red ginseng extract hydrolyzed by pectinase may effectively alleviate oxidative stress‐mediated memory deficits possibly through Nrf2‐related detoxification.Support or Funding InformationThis work was supported by the Food Functionality Evaluation program funded by the Ministry of Agriculture, Food and Rural Affairs through Korea Food Research Institute.
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