HIF/EPO信号途径对红景天苷在缺血性脑损伤大鼠的神经保护和调节突触可塑性作用的研究

项目名称： HIF/EPO信号途径对红景天苷在缺血性脑损伤大鼠的神经保护和调节突触可塑性作用的研究

项目编号： No.81473382

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 洪桂祝

作者单位： 福建中医药大学

项目金额： 70万元

中文摘要： 课题组前期研究表明红景天苷在大脑中动脉栓塞(MCAO)再灌注大鼠模型具有神经保护作用；提高HIF-1α水平，诱导一系列受EPO调控，包括与突触可塑性相关的基因。那么，红景天苷是否同时具有神经保护和调节突触可塑性的作用；HIF-1α/HIF-2α/EPO信号途径能否调控该作用？本研究通过不同时点注射给药，测量神经损伤，梗死体积，长时程增强（LTP）和上述基因的表达，研究红景天苷在MCAO再灌注大鼠中的时效关系。在此基础上,通过侧脑室注射HIF-1α、HIF-1α/2α抑制剂或可溶性EPO受体后造模，给药，测量以上指标，研究HIF信号途径对红景天苷作用的影响。并以原代培养大鼠皮质神经细胞缺氧缺糖损伤为模型，研究红景天苷对神经细胞的作用；用RNAi方法敲除HIF-1α，HIF-2α或EPO受体，研究该信号途径对红景天苷作用的影响。本项目对认识传统中药红景天及其有效成分红景天苷在脑卒中的药理作用有重要意义。

中文关键词： 红景天；红景天苷；脑卒中；神经保护；突触可塑性

英文摘要： Salidroside is a bioactive component of Rhodiola rosea, which has been used for treating stroke in traditional Chinese medicine. Our previous studies have revealed that salidroside was neuroprotective after transient middle cerebral artery occlusion (MCAO) of rats, and induced Egr1, Egr2, Egr4, Arc, Vgf, Hbb-b1, Hbb and Hba-a genes. It is known that all these genes are associated with neuroprotection or modulation of synaptic plasticity and can be induced by erythropoietin (EPO). Our preliminary data showed that salidroside also increased HIF-1α protein level, which could in turn cause increased EPO transcription. The purpose of the present studies is to investigate whether salidorside exerts neuroprotective and neuroplasitic effects that depend on HIF-1α/HIF-2α/EPO signaling. We will firstly investigate the optimum treatment period over which salidroside exerts neuroprotection, modulation of long-term potentiation (LTP) and regulation of the expression of NMDA receptor, AMPA receptor, Egr1, Egr2, Egr4, Arc, Vgf, Hbb-b1, Hbb and Hba-a genes after MCAO in rats. Animals will be treated with salidroside (50mg/kg/d)for 2h, 1d, 2d, 3d or 6d, after MCAO, and neurological deficit scores, infarct volumes, LTP and cerebral gene expression will be measured. We will then determine whether the effects of salidroside are dependent on activation of HIF-1α/HIF-2α/EPO signaling. Rats will be injected with either HIF-1α inhibitor or HIF-1α/2α inhibitor or recombinant soluble form of EPO receptor, or carrier alone, into the lateral ventricle of brain prior to MCAO. The rats will then be treated with salidroside over the previously determined optimum period, and neurological deficit scores, infarct volumes, LTP and cerebral gene expression will again be measured. In addition, we will investigate effects of salidroside on neuroprotection and regulation of cerebral gene expression in primary cultures of rat cortical neurons under conditions of oxygen-glucose deprivation (OGD); and whether depletion of HIF-1α, HIF-2α and EPO receptor with target-specific RNAi would inhibit the effects of salidroside and alter cerebral gene expression. The results of this study will have significant impact on the understanding of the molecular mechanisms of action of salidroside and Rhodiola rosea in stroke.

英文关键词： Rhodiola rosea;salidroside;stroke;neuroprection;synaptic plasticity