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.

Ghrelin Improves Antioxidant Defense in Blood and Brain in Normobaric Hypoxia in Adult Male Rats

“…18 In addition, ghrelin has several antiinflammatory properties and decreases neuronal apoptosis. [19][20][21][22] Antioxidant properties of ghrelin have also been demonstrated in recent studies. [23][24][25] Therefore, the aim of this study was to evaluate the effects of ghrelin on the blood levels of MDA and TAC and brain levels of MDA, SOD, GPx and CAT in the normobaric systemic hypoxia situation in rats.…”

Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

“…Neuroprotective effects of ghrelin have been recently reported in rodent model of focal cerebral ischemia (Chung et al 2007, Miao et al 2007, in which systemic administration of ghrelin augmented the expression of Bcl2/Bax and heat shock protein 70 and inhibited prostate apoptosis response-4, caspase-8, -9, and -3. In addition, we demonstrated the in vitro neuroprotective effect of ghrelin in neurons, which was associated with the inhibition of the apoptotic cascade and preservation of mitochondrial integrity (Chung et al 2007(Chung et al , 2008.…”

“…injection of ghrelin (80 mg/kg) 30 min prior to KA injection, and a second ghrelin treatment was performed 24 h after the KA injection. In this study, 80 mg/kg of ghrelin was chosen on the basis of our previous studies that this dose of ghrelin exerted a potent neuroprotective action (Chung et al 2007). To examine whether the effect of ghrelin is exerted through GHSR1a, animals were co-treated with D-Lys-GHRP-6 (1 mg/kg, i.p.)…”

“…In addition to stimulating GH release from the anterior pituitary and inducing a positive energy balance by stimulating food intake while decreasing fat usage through GH-independent mechanisms (Kojima et al 1999, Peino et al 2000, we recently reported that ghrelin acts as a survival factor for neurons in vivo and in vitro by inhibiting apoptotic pathways (Chung et al 2007). Moreover, ghrelin receptor, GH secretagogue receptor type 1a (GHSR1a), is expressed in the hippocampal neurons (Guan et al 1997), and ghrelin protects hippocampal neurons against ischemic injury (Liu et al 2006(Liu et al , 2009.…”

Differential effects of GH and GH-releasing peptide-6 on astrocytes

“…In previous studies, we demonstrated that rats treated with GH or GHRP-6 showed increased levels of phosphorylated Akt but not of ERK1/2 in the hypothalamus, hippocampus and cerebellum (Frago et al 2002); although in some circumstances, GH and ghrelin have been shown to activate not only the PI3K/Akt signalling pathway but also the MAPK pathway (Chung et al 2007, Brooks et al 2008, Andrews 2011. Thus, GH after binding to its receptor activates the PI3K/Akt signalling pathway (Frago et al 2002), which could induce the activation and differentiation of astrocytes in the hypothalamus and hippocampus.…”