Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat
Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat
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DOI：
10.1097/00004647-200202000-00005
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发表时间：
2002-02-01
影响因子：
6.3
通讯作者：
Park, DS
中科院分区：
文献类型：
--
作者：
Wang, FH;Corbett, D;Park, DS
越来越多的证据表明细胞周期蛋白依赖性激酶参与了体外多种应激诱导的神经元死亡。然而，它们在体内细胞死亡范例中的作用还没有得到很好的表征。因此，作者研究了细胞周期蛋白依赖性激酶抑制是否在全脑缺血模型中导致功能相关和持续的神经保护。脑室内给药的细胞周期蛋白依赖性激酶抑制剂flavopiridol，立即或在4小时后再灌注后，全球侮辱，减少损伤时，在CA1海马再灌注后7天检查。再灌注后8小时给予flavopiridol时，未观察到明显的保护作用。肿瘤抑制视网膜母细胞瘤蛋白，细胞周期蛋白依赖性激酶的底物，磷酸化的细胞周期蛋白依赖性激酶的共识网站后，全球侮辱，这种磷酸化抑制flavopiridol管理。重要的是，flavopiridol对核心体温没有影响，表明神经保护机制是通过细胞周期蛋白依赖性激酶抑制，而不是通过低温。此外，抑制细胞周期蛋白依赖性激酶改善空间学习行为，通过Morris水迷宫评估7至9天后再灌注。然而，在再灌注后28天，在第7天观察到的组织学保护不存在。这些结果表明，细胞周期蛋白依赖性激酶抑制提供了一个延长的时间形态和功能的神经保护，可能会允许其他神经保护方式引入的时间。
Increasing evidence suggests that cyclin-dependent kinases participate in neuronal death induced by multiple stresses in vitro. However, their role in cell death paradigms in vivo is not well characterized. Accordingly, the authors examined whether cyclin-dependent kinase inhibition resulted in functionally relevant and sustained neuroprotection in a model of global ischemia. Intracerebroventricular administration of the cyclin-dependent kinase inhibitor flavopiridol, immediately or at 4 hours postreperfusion after a global insult, reduced injury in the CA1 of the hippocampus when examined 7 days after reperfusion. No significant protection was observed when flavopiridol was administered 8 hours after reperfusion. The tumor-suppressor retinoblastoma protein, a substrate of cyclin-dependent kinase, was phosphorylated on a cyclin-dependent kinase consensus site after the global insult; this phosphorylation was inhibited by flavopiridol administration. Importantly, flavopiridol had no effect on core body temperature, suggesting that the mechanism of neuroprotection was through cyclin-dependent kinase inhibition but not through hypothermia. Furthermore, inhibition of cyclin-dependent kinases improved spatial learning behavior as assessed by the Morris water maze 7 to 9 days after reperfusion. However, the histologic protection observed at day 7 was absent 28 days after reperfusion. These results indicate that cyclin-dependent kinase inhibition provides an extended period of morphologic and functional neuroprotection that may allow time for other neuroprotective modalities to be introduced.