Ghrelin is an endogenous ligand for growth hormone (GH) secretagogue receptor 1a (GHS-R1a) and is produced and released mainly from the stomach. It was recently demonstrated that ghrelin can function as a neuroprotective factor by inhibiting apoptotic pathways. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of Parkinson's disease (PD) neurodegeneration. However, the role of microglia in the neuroprotective properties of ghrelin is still unknown. Here we show that, in the mouse MPTP PD model generated by an acute regimen of MPTP administration, systemic administration of ghrelin significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers through the activation of GHS-R1a. We also found that ghrelin reduced nitrotyrosine levels and improved the impairment of rota-rod performance. Ghrelin prevents MPTP-induced microglial activation in the SNpc and striatum, the expression of pro-inflammatory molecules tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and the activation of inducible nitric oxide synthase. The inhibitory effect of ghrelin on the activation of microglia appears to be indirect by suppressing matrix metalloproteinase-3 (MMP-3) expression in stressed dopaminergic neurons because GHS-R1a is not expressed in SNpc microglial cells. Finally, in vitro administration of ghrelin prevented 1-methyl-4-phenylpyridinium-induced dopaminergic cell loss, MMP-3 expression, microglial activation, and the subsequent release of TNF-alpha, IL-1beta, and nitrite in mesencephalic cultures. Our data indicate that ghrelin may act as a survival factor for dopaminergic neurons by functioning as a microglia-deactivating factor and suggest that ghrelin may be a valuable therapeutic agent for neurodegenerative diseases such as PD.
Rapid CommuniCationis principally released from Gr cells in the oxyntic mucosa of the stomach [5]. In addition to stimulating GH release via the hypothalamus and direct pituitary pathways and inducing a positive energy balance by stimulating food intake while decreasing fat use through GH-independent mechanisms, ghrelin has been suggested to have numerous peripheral actions including direct effects on exocrine and endocrine pancreatic functions, carbohydrate metabolism, the cardiovascular system, gastric secretion, stomach motility, and sleep [6]. It has been reported that maternal ghrelin plays an important role in rat fetal development during pregnancy [7]. Ghrelin is also involved in neurogenesis of the rat fetal spinal cord [8]. In addition, in the nucleus of the solitary tract (NTS) [9] and the dorsal motor nucleus of vagus (DMNV) [10] in adult rats with cervical vagotomy, ghrelin promotes neural proliferation in vivo and in vitro. Moreover, very recently it has been reported that ghrelin increases cellular proliferation of adult rat hippocampal progenitor cells in vitro [11]. However, there is no report to date about the effect of ghrelin on neurogenesis in the adult mammalian SGZ of the DG in vivo. In the present study, we wanted to study the impact of systemically administered ghrelin. Therefore, the aim of this study was to investigate the proliferation and differentiation of Medicine, Seoul, Korea abstract. The aim of our study was to investigate the effect of the peripheral administration of ghrelin, a peptide hormone secreted from the stomach, on cellular proliferation and differentiation of progenitor cells in the adult hippocampus. Double immunohistochemical staining revealed that ki-67-positive hippocampal progenitor cells expressed ghrelin receptors. In mice treated with ghrelin (80 µg/kg, i.p.) for 8 days, bromodeoxyuridine incorporation and doublecortin-positive neuroblasts were significantly increased in the dentate subgranular zone. We also found that the numbers of bromodeoxyuridine-and doublecortin-immunoreactive cells were significantly reduced after anti-ghrelin antibody (10 µg/kg, i.p.) treatment for 8 days. Therefore, our results indicate that ghrelin induces proliferation and differentiation of adult hippocampal progenitors, suggesting an involvement of ghrelin in hippocampal neurogenesis.
Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.
Abstract. ghrelin is known to promote neuronal defense and survival against ischemic injury by inhibiting apoptotic processes. in the present study, we investigated the role of prostate apoptosis response-4 (Par-4), a proapoptotic gene the expression of which is increased after ischemic injury, in ghrelin-mediated neuroprotection during middle cerebral artery occlusion (MCao). Both ghrelin and des-acyl ghrelin protected cortical neurons from ischemic injury. ghrelin receptor specific antagonist abolished the protective effects of ghrelin, whereas those of des-acyl ghrelin were preserved, suggesting the involvement of a receptor that is distinct from gHS-r1a. The expression of Par-4 was increased by MCao, which was attenuated by ghrelin and des-acyl ghrelin treatments. Both ghrelin and des-acyl ghrelin increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. our data indicate that des-acyl ghrelin, as well as ghrelin, protect cortical neurons against ischemic injury through the inhibition of Par-4 expression and apoptotic molecules in mitochondrial pathway.
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