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

在沙鼠前脑缺血前2小时或3分钟后，将前列腺素I2类似物TEI-7165输注到沙鼠侧脑室7天，已知可预防海马CA1区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小时开始脑室内输注TEI-7165是否能拯救海马CA1神经元，以及TEI-7165对缺血海马CA1神经元的保护作用机制尚不清楚。在本实验的第一组实验中，沙鼠在前脑缺血3 min后72小时向侧脑室注入TEI-7165，持续28天。TEI-7165输注对缺血学习障碍的预防作用呈剂量依赖性。随后的光镜检查显示，输注TEI-7165的沙鼠海马CA1区的锥体神经元数量明显多于接受载药输注的沙鼠。在本实验的第二组中，TEI-7165以浓度依赖的方式阻止一氧化氮（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。TEI-7165 （10^<-3> ~ 10^<-1> fg/ml）可抑制Bcl-2家族促凋亡蛋白Bax的表达。因此，本研究表明TEI-7165可能通过抑制促凋亡因子Bax的表达，对体内缺血海马神经元具有有效的神经保护作用。

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.