CDK5 inhibitors prevent astroglial apoptosis and reactive astrogliosis by regulating PKA and DRP1 phosphorylations in the rat hippocampus
CDK5 inhibitors prevent astroglial apoptosis and reactive astrogliosis by regulating PKA and DRP1 phosphorylations in the rat hippocampus
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DOI：
10.1016/j.neures.2017.01.006
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发表时间：
2017-06-01
影响因子：
2.9
通讯作者：
Kim, Ji-Eun
中科院分区：
文献类型：
--
作者：
Hyun, Hye-Won;Min, Su-Ji;Kim, Ji-Eun
状态癫痫症（SE）导致与动力蛋白相关蛋白1（DRP1）介导的线粒体动力学的独特模式，该动力学与代表差异胶质体性质的区域特异性模式中与星形胶质细胞凋亡和反应性星形胶质细胞相关。然而，在此过程中，DRP1磷酸化的表型/上游效应子的定义较低。由于Cyclin依赖性激酶5（CDK5）参与反应性星形胶质细胞增多症，因此CDK5是DRP1磷酸化的可能上游调节剂之一。在本研究中，Olomoucine和Roscovitine（CDK5抑制剂）都有效地改善了齿状回的SE诱导的星形胶质细胞凋亡，而不会改变癫痫发作易感性。此外，它们抑制了与SE诱导的神经元死亡无关的CA1区域的反应性星形胶质细胞增多症。 CDK5抑制剂的这些作用与消除SE诱导的DRP1磷酸化率和线粒体长度的消除有关。 CDK5抑制剂在星形胶质细胞中还负调控蛋白激酶A（PKA）活性。因此，我们的发现表明CDK5抑制剂可能会减轻星形胶质细胞凋亡和反应性星形胶质细胞增多，并伴随DRP1介导的线粒体动力学的调节。 （c）2017年其他爱尔兰有限公司和日本神经科学学会。版权所有。
Status epilepticus (SE) results in the unique pattern of dynamin-related protein 1 (DRP1)-mediated mitochondrial dynamics, which is associated with astroglial apoptosis and reactive astrogliosis in the regional-specific pattern representing the differential astroglial properties. However, less defined are the epiphenomena/upstream effecters for DRP1 phosphorylation in this process. Since cyclin-dependent kinase 5 (CDK5) is involved in reactive astrogliosis, CDK5 is one of the possible upstream regulators for DRP1 phosphorylation. In the present study, both olomoucine and roscovitine (CDK5 inhibitors) effectively ameliorated SE-induced astroglial apoptosis in the dentate gyrus without changed seizure susceptibility. In addition, they inhibited reactive astrogliosis in the CA1 region independent of neuronal death induced by SE. These effects of CDK5 inhibitors were relevant to abrogation of altered DRP1 phosphorylation ratio and mitochondrial length induced by SE. CDK5 inhibitors also negatively regulated protein kinase A (PKA) activity in astrocytes. Therefore, our findings suggest that CDK5 inhibitors may mitigate astroglial apoptosis and reactive astrogliosis accompanied by modulations of DRP1-mediated mitochondrial dynamics. (C) 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.