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Molecular Mechanism of slowly progressive neuronal degeneration after brief ischemia

短暂缺血后缓慢进行性神经元变性的分子机制

基本信息

批准号：
14571315
负责人：
DESAKI Junzo
金额：
$ 2.18万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Slowly progressive degeneration of the hippocampal CA1 neurons was induced by a three-minute transient global ischemia in gerbils. Sustained degeneration of hippocampal CA1 neurons was evident in one month after ischemia. To investigate the effects of an 18-mer-peptide comprising the hydrophilic sequence of the rat saposin C domain (18MP) on this sustained, neuronal degeneration, an intracerebroventricular 18MP infusion was initiated three days after ischemia. Histopathological and behavioral evaluations were conducted one week and one month after induction of ischemia. When compared to the vehicle infusion, 18MP treatment significantly increased the response latency time in a passive avoidance task. Increased neuronal density was also evident as was the number of intact synapses in the hippocampal CA1 region at one week. and one month after ischemia. 18MP treatment also significantly decreased the number of TUNEL-positive CA1 neurons one week after ischemia. Subsequent in vitro experiments using cultured neurons demonstrated that the 18MP at optimal extracellular concentrations of 1-100 fg/ml prevented nitric oxide (NO)-induced neuronal damage as expected and significantly upregulated the expressions of bcl-xL mRNA and its translated protein. These results suggest that the gerbil model of ischemia of a 3-minute duration is useful in studying the pathogenesis of slowly progressive neuronal degeneration following stroke and for evaluating effects of novel therapeutic. agents. It is likely that the 18MP at the low extracellular concentrations prevents neuronal apoptosis possibly through upregulation of the mitochondrial anti-apoptotic factor Bcl-xL.

采用沙土鼠全脑缺血3分钟，造成海马CA 1区神经元缓慢进行性变性。海马CA 1区神经元在缺血后1个月持续变性明显。为了研究包含大鼠saposin C结构域的亲水性序列的18-mer-肽（18 MP）对这种持续的神经元变性的影响，在缺血后三天开始脑室内18 MP输注。在诱导缺血后一周和一个月进行组织学和行为学评价。与溶媒输注相比，18 MP处理显著增加了被动回避任务中的反应潜伏期。增加的神经元密度也是明显的，在海马CA 1区的完整突触的数量在一周。缺血后1个月。18 MP治疗还显著减少缺血后一周的TUNEL阳性CA 1神经元的数量。随后使用培养的神经元的体外实验表明，在1-100 fg/ml的最佳细胞外浓度的18 MP防止一氧化氮（NO）诱导的神经元损伤的预期和显着上调bcl-xL mRNA及其翻译蛋白的表达。这些结果表明，沙鼠模型的缺血3分钟的时间是有用的，在研究发病机制的缓慢进行性神经元变性中风后，并评估新的治疗效果。剂.低细胞外浓度的18 MP可能通过上调线粒体抗凋亡因子Bcl-xL来防止神经元凋亡。