Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea.
Cells. 2019 Jul 19;8(7):746. doi: 10.3390/cells8070746.
Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-κB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.
在生理条件下，小胶质细胞是驻留在大脑中的独特免疫细胞，它被血脑屏障与系统性免疫系统隔离开来。在癫痫持续状态（SE，长时间的癫痫发作）后，小胶质细胞被迅速激活，并且血液来源的单核细胞浸润到大脑中；因此，小胶质细胞激活和单核细胞浸润的调节是抑制 SE 不良后果的主要治疗策略之一。罗司维亭（Roscovitine），一种有效的（但非选择性的）细胞周期蛋白依赖性激酶 5（CDK5）抑制剂，在几种体内模型中被发现具有抗炎和抑制小胶质细胞的作用，尽管其潜在机制尚未阐明。在本研究中，罗司维亭减轻了 SE 诱导的前额顶叶皮层（FPC）单核细胞浸润，而没有血管源性水肿形成，同时降低了驻留小胶质细胞中单核细胞趋化蛋白-1（MCP-1）和溶酶体相关膜蛋白 1（LAMP1）的表达，而不影响小胶质细胞向阿米巴样形态的转化。此外，罗司维亭改善了 p38 丝裂原激活蛋白激酶（p38 MAPK）磷酸化的上调，但不影响核因子-κB-S276 磷酸化。与罗司维亭类似，p38 MAPK 抑制剂 SB202190 减轻了 SE 后 FPC 中的单核细胞浸润和小胶质细胞中 MCP-1 和 LAMP1 的表达。因此，这些发现首次表明，罗司维亭可能通过调节 p38 MAPK 介导的小胶质细胞反应来抑制 SE 诱导的神经炎症。
