【作者】 夏青； 郑焱； 夏作理； 祝世功；

【Author】 Qing Xia, Wei Panga, Zuo-Li Xiab, Ski-Gong Zhua a Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083, P R China; b Institiute of Brain Microculation, Taishan Medical College, Taian 271000, Shandong Province, P R China

【机构】 北京大学医学部生理与病理生理学系； 山东泰山医学院脑微循环研究所；

【摘要】 <正>Ghrelin是新发现的一种28个氨基酸的脑肠肽,广泛分布于中枢神经系统、消化系统和其它组织。目前关于ghelin对中枢神经系统作用的研究主要集中在下丘脑—垂体系统,而对中枢神经系统其它部位的研究报道尚不多。尤其是在脑缺血等病理情况下,ghelin对缺血脑区神经元的更多还原

【Abstract】 Ghrelin is a 28-amino acid gut-brain peptide predominantly produced by the stomach, displayed strong growth hormone (GH)-releasing activity mediated by the hypothalamus-pituitary GH secretagogus (GHS)-receptors. Ghrelin exerts many biologically activities which focuses on the hypothalamus-pituitary unit and peripheral tissues. The aim of the present study is to evaluate the neuroprotective effects of ghrelin on the ischemic penumbra in focal cerebral infraction. We examined the blood flow and the potential mechanism of infarct reduction by ghrelin, especially effects on apoptosis within the ischemia brain. Focal ischemia induced by photochemically thrombotic distal middle cerebral artery (dMCA) occlusion model to adult rats results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. The effects of ghrelin on regional cerebral blood flow (rCBF) in penumbra areas used by a laser Doppler Flowmeter. The rCBF in ischemic penumbra was increased pulsantly, and then stabilized on twice value of ischemic baseline after intraventricular administration (ICV) of ghrelin. The measurement of NO and NOS concentration in the ischemic core and penumbra were performed at 1h after brain infarct. The results demonstated that the increasing NO concentration was not the main cause of blood flow in penumbra.The expression and subcellular distribution of several proteins involved in apoptosis have been examined in the penumbra and in the infarct core by using combined methods of immunohistochemistry and Western blotting. Photochemical ischemia results in activation of complex signal pathways for cell death in the penumbra. Increased expression of Bcl-2, Bax, HSP70 and NF-κB occurs and the active caspase-3, caspase-8, caspase-9, phospho-ERK1/2 and phospho-p38 were observed following ischemia and together indicate the activation of the caspase-dependent pathway of apoptosis in the penumbra. The expression of HSP70 and NF-κB were restricted to the penumbra. The results showed that ghrelin signigicantly reduced infarct volume and the number of Tunel-positive brain cells in ischemic penumbra. Western blotting analysis and immunohistochemistry demonstrated that pro-treatment with ghrelin could significantly inhibit the caspase-3, caspase-9, phospho-ERK1/2 and phospho-p38 expression and enhance Bcl-2 and HSP70 expression in the ischemic penumbra (p<0.05). In addition, no significant changes in Bax, caspase-8 and NF-κB proteins of ghrelin-compared to vehicle-treated animals. These findings suggested that the mechanism for in vivo neuroprotection by ghrelin is, in part, mediated by caspase activation leading to apoptotic cell death. The present findings provide strong evidence for an involvement of ghrelin-mediated brain protection following focal cerebral ischemia.The study brings to light some noval mechanism of ghrelin protective effects on ischemia brain damages. Thus, ghrelin may be useful in the treatment of stroke and possibly other apoptosis associated acute and chronic injuries to the brain更多还原