【作者】 陈力学；

【导师】 康格非； 刘宝松；

【作者基本信息】 重庆医科大学 ， 临床检验诊断学， 2006， 博士

【摘要】 脑血管疾病已成为世界上危害人类健康的主要疾病之一,有较高的发病率和死亡率。目前对脑血管疾病、脑缺氧损伤及继发性脑损害的研究已涉及很多方面,但其发病机制仍不十分清楚。近年来,脑缺血临床治疗虽然取得很大进展,但其治疗效果仍不令人满意,特别是离子通道阻断剂类药物有明显的副作用,在临床应用中有较大的局限性;因此,亟待从特异性病理性离子通道阻断治疗进行深入研究和探索。谷氨酸(Glu)大量释放是脑缺血性损伤的重要发病机制。谷氨酸受体分NMDA受体、AMPA受体和海藻氨酸(KA)受体三个亚类。NMDA受体过度激活与Ca2+超载是神经元缺血性损伤的主要原因,也是脑缺血病理发展过程中的重要环节。现已发现NMDAR至少存在7个亚单位,即NR1亚单位、4种NR2亚单位(分为NR2A、NR2B、NR2C和NR2D)以及2种NR3亚单位。NMDA受体上有磷酸化位点和通道阻断剂等结合位点,缺血损伤后NMDA受体激活可介导Ca2+内流和胞内Ca2+超载,引发一系列病理变化过程,导致细胞损伤和凋亡。NMDA受体的功能结构基础主要位于NR2B上,NR2B在中枢神经系统中具有广泛的分布,在突触可塑性、皮质和海马神经元长时程增强效应(Long-term potentiation,LTP)和学习记忆中扮演了非常重要的角色。通过电生理更多还原

【Abstract】 Cerebrovascular disease, with both high morbidity and mortality, is a serious hazard to human health and ranks as the third disease leading to death. The pathogenesis mechanisms about cerebrovascular disease, cerebral anoxia injury and secondary brain damage are unclear at present. Recent studies suggest that some channel blocking drugs and inhibitors in cerebral ischemia give good therapy results, but usually accompanying side effects in different degrees . Thus, to explore special drugs blocking ion channel is of necessity. The excitatory toxicity of glutamic acid is one of the important reasons of secondary injury after cerebral trauma or ischemic injury, in which the Ca2+ intracellular overload is the main pathogenesis.The N-methyl-D-aspartate receptor (NR), a subtype of ion-tropic glutamate receptor, provides sites for phosphorylation and for channel blocking. NRs are composed of NR1 and NR2A-D subunits. Activity of NMDA receptor after ischemic injury will mediate Ca2+ inward influx and Ca2+ overload, which leads to neuronal injury and apoptosis and induce pathological changes. NR2B, which is the primary modulating subunits of NMDARs, distributes extensively. NR2B subunit plays a crucial role in excitatory synaptic transmission and neuronal excitotoxicity of the CNS, especially synaptic plasticity, long-term potentiation (LTP) as well as learning and memory ability. Tyrosine phosphorylation of NR2B plays an important role in Ca2+ inward influx, which leads to neuronal injury.更多还原