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Protection of the ischemic brain by a new prostaglandin I2 analog clinprost

新型前列腺素 I2 类似物 clinprost 对缺血性大脑的保护

基本信息

批准号：
10557128
负责人：
SAKANAKA Masahiro
金额：
$ 7.42万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

The 7-day infusion of a prostaglandin I2 analog TEI-7165 into the lateral ventricle of gerbils starting 2 hours before or just after 3-min forebrain ischemia is known to prevent the occurrence of learning disability and neuronal death in the hippocampal CA1 field. However, it remains to be determined whether or not intracerebroventricular infusion of TEI-7165 starting 72 hours after 3-min forebrain ischemia rescues hippocampal CA1 neurons, and the mechanism (s) by which TEI-7165 exerts a protective effect on ischemic hippocampal CA1 neurons also remains to be determined. In the first set of the present experiments, gerbils were infused with TEI-7165 for 28 days into the lateral ventricle at 72 hours after 3-min forebrain ischemia. TEI-7165 infusion prevented the occurrence of ischemia-induced learning disability in a dose-dependent manner as revealed by the step-down passive avoidance task. Subsequent light microscopic examinations showed that pyramidal neurons in the CA1 region of the hippocampus were significantly more numerous in gerbils infused with TEI-7165 than in those receiving vehicle infusion. In the second set of the present experiments, TEI-7165 prevented in vitro neuronal apoptosis or apoptotic neuron death caused by the nitric oxide (NO) donor sodium nitroprusside (SNP) in a concentration-dependent manner. Moreover, TEI-7165 (10^<-3>〜10^<-1> fg/ml) inhibited the expression of Bax, a proapoptotic Bcl-2 family protein, in cultured neurons. Thus, the present study indicates a potent neuroprotective effect of TEI-7165 on ischemic hippocampal neurons in vivo possibly through inhibition of the expression of the proapoptotic factor, Bax.

已知在前脑缺血3分钟之前或之后2小时开始将前列腺素I2类似物TEI-7165输注到沙鼠的侧脑室中7天，以防止海马CA 1场中学习障碍和神经元死亡的发生。然而，在前脑缺血3分钟后72小时开始的TEI-7165的脑室内输注是否拯救海马CA 1神经元仍有待确定，并且TEI-7165对缺血海马CA 1神经元发挥保护作用的机制也有待确定。在本实验的第一组中，在前脑缺血3分钟后72小时，将TEI-7165输注到沙鼠的侧脑室中28天。TEI-7165输注以剂量依赖性方式防止缺血诱导的学习障碍的发生，如通过逐步下降的被动回避任务所揭示的。随后的光学显微镜检查显示，海马CA 1区的锥体神经元在注入TEI-7165的沙鼠中的数量明显多于接受溶媒注入的沙鼠。在本实验的第二组中，TEI-7165以浓度依赖性方式防止由一氧化氮（NO）供体硝普钠（SNP）引起的体外神经元凋亡或凋亡性神经元死亡。此外，TEI-7165（10 <-3>μ <-1>g/ml）抑制培养神经元中促凋亡Bcl-2家族蛋白Bax的表达。因此，本研究表明TEI-7165对体内缺血海马神经元的有效神经保护作用可能通过抑制促凋亡因子Bax的表达。