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.

众所周知，前2小时或之后，将前列腺素I2类似物TEI-7165注入到毛比尔的横向通气中的7天注输注，以防止在海马CA1场中发生学习障碍和神经元死亡的发生。然而，在3分钟前脑缺血后72小时开始，脑室内注入TEI-7165是否尚待确定，救出海马CA1神经元，以及TEI-7165通过该机制对Inchampocampal CA1神经元发挥保护作用的机制也仍然是确定的。在本实验的第一组实验中，在3分钟前脑缺血后72小时，在横向通风中注入TEI-7165，持续28天。 TEI-7165输注阻止了逐步降低的被动回避任务所揭示的剂量依赖性方式缺血诱导的学习障碍的发生。随后的光学显微镜检查表明，在注入TEI-7165的沙鼠中，海马CA1区域中的锥体神经元要比接收车辆输注的锥体神经元要多得多。在本实验的第二组实验中，TEI-7165阻止了一氧化氮（NO）供体硝化钠（SNP）以浓度依赖性方式引起的体外神经元细胞凋亡或凋亡神经元死亡。此外，TEI-7165（10^<-3> 〜10^<-1> fg/ml）在培养的神经元中抑制了Bax（一种促凋亡的Bcl-2家族蛋白）Bax的表达。这是本研究表明，通过抑制促凋亡因子的表达，TEI-7165对体内缺血性海马神经元的潜在神经保护作用。