Hyun Hye-Won, Min Su-Ji, Kim Ji-Eun
Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Kangwon-Do 24252, South Korea.
Neurosci Res. 2017 Jun;119:24-37. doi: 10.1016/j.neures.2017.01.006. Epub 2017 Jan 30.
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.
癫痫持续状态（SE）导致动力相关蛋白1（DRP1）介导的独特线粒体动力学模式，这与星形胶质细胞凋亡和反应性星形胶质细胞增生有关，呈现出代表不同星形胶质细胞特性的区域特异性模式。然而，在此过程中，DRP1磷酸化的附带现象/上游效应器尚不清楚。由于细胞周期蛋白依赖性激酶5（CDK5）参与反应性星形胶质细胞增生，CDK5是DRP1磷酸化的可能上游调节因子之一。在本研究中，olomoucine和roscovitine（CDK5抑制剂）均有效改善了SE诱导的齿状回星形胶质细胞凋亡，且未改变癫痫易感性。此外，它们抑制了CA1区的反应性星形胶质细胞增生，而与SE诱导的神经元死亡无关。CDK5抑制剂的这些作用与消除SE诱导的DRP1磷酸化比率改变和线粒体长度有关。CDK5抑制剂还对星形胶质细胞中的蛋白激酶A（PKA）活性产生负调节作用。因此，我们的研究结果表明，CDK5抑制剂可能通过调节DRP1介导的线粒体动力学来减轻星形胶质细胞凋亡和反应性星形胶质细胞增生。
