【作者】 刘睿；

【导师】 张岫美；

【作者基本信息】 山东大学 ， 药理学， 2006， 硕士

【摘要】 缺血性脑血管病是严重危害人类生命与健康的常见病和多发病，具有“三高一低”的发病特点，即高发病率、高致残率、高复发率和低死亡率，是中老年人致死和致残的主要疾病。在人类各种疾病死因的排序中，脑血管病一直列于前三位之内，成为人类死亡的主要原因之一。而且，由于生活水平的提高和老年人口的不断增加，脑血管病的发病率仍在不断上升。但因其发病机制复杂，部位特殊，至今仍无有效的理想治疗药物，因此积极寻找有效药物，降低发病率和致残率是医学工作者研究的重点课题。众所周知，对于缺血性脑血管疾病，溶栓及脑保护治疗仍然是当今治疗的两大趋势，而中药及其有效成分在缺血性脑血管病治疗中的作用正逐渐受到重视。近年的研究显示，缺血可导致脑损伤，恢复血供后还可导致进一步的损伤，脑缺血再灌注后，神经元的损伤反而更加严重，即所谓的迟发性神经元死亡。目前，随着其他器官组织特别是心肌缺血再灌损伤概念的确立，脑缺血再灌注损伤概念也逐渐发展起来。缺血性脑损伤的机理目前已提出若干学说，如兴奋性氨基酸毒性学说、钙超载学说、氧自由基学说和酸中毒学说等。在这些学说中，兴奋性氨基酸毒性学说具有重要的地位，并且其他学说都与它有着不同的联系。目前，脑卒中时脑细胞的死亡已从“血供中止→无底物→无能量→细胞死亡”的认识，向急性缺血性脑损伤存在损伤级联反应的认识过渡，这其中至少涉及4个不同的机制：兴奋毒性、梗死区周围去极化、炎症和程序性细胞死亡，其间有重叠并互相联系。级联反应都从兴奋毒性开始，兴奋毒性是缺血性脑损伤最关键、最重要的环节，如果有效而迅速地阻断级联反应，不仅能提高急性缺血性脑卒中的临床疗效，为溶栓和降纤提供条件，而且可以延长成功再灌注的时间窗。EAA必须通过激活突触后膜兴奋性氨基酸受体起作用，因此，兴奋毒性的核心是兴奋性氨基酸受体的激活。大鼠神经元有多种类型的兴奋性氨基酸（EAA）受体，按其对不同激动剂的选择性，一般分为N-甲基D-天冬氨酸（NMDA）型、α-氨基羟甲基恶唑丙酸（AMPA）型及其他代谢性受体。NMDA受体是配体门控性Ca²⁺通道，对Ca²⁺有较强更多还原

【Abstract】 lschemic cerebrovascular disease (ICVD) is usually a consequence of atherosclerosis and is the commonest cause of stroke. With high morbidity, high disability rate, high recurrence rate and low mortality, cerebrovascular disease has been one of the most devastating epidemics of our time. As we know, thrombolytic therapy and protective therapy of drug are still the major measurement in the treatment of ischemic brain vascular diseases at present, and the protective effects of Chinese traditional medicines are being paid more and more attention to. Recent study has revealed that N-methyl-D-aspartate (NMDA) receptors, a subclass of excitatory amino acid receptors, may play an important role in ICVD. Nowadays, theory of acute cerebral accident is transitional from the cognition of "blood suspension→no substrate→energy failure→cell death" to the theory of neurotoxicity cascade reaction, at least including four different but interconnected mechanisms: exitotoxicity, infarction surrounding depolarization, inflammation and programmed cell death. Cascade reaction is initiated from exitotoxicity; that is, exitotoxicity is the most important process in the accidence of acute cerebral injury. Recently excitotoxicity has been described in virtually every region of the CNS and is thought to stimulate a series of linked events that lead to cell death of ischemic cerebrovascular vascular disease. The NMDA receptor is a heteromenc structure consisting of four or five subunits. Assembly of a functional receptor requires the presence of an NRl subunit, which is derived from a single gene and exists in at least eight different splice variant forms, along with one or more NR2 subunits (NR2A, NR2B, NR2C and NR2D) and/or a NR3 subunit, all derived from separate genes. Recombination studies have shown that the combination of an NRl subunit with a NR2 or NR3 subunit results in a functional更多还原