富含亮氨酸重复激酶 2 通过调控 P38 MAPK/Drosha 通路加重大鼠脑出血后继发脑损伤。
Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway.
机构信息
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Juqian Street, Changzhou, Jiangsu Province 213003, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China; Department of Neurosurgery, The affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu Province 212001, China.
出版信息
Neurobiol Dis. 2018 Nov;119:53-64. doi: 10.1016/j.nbd.2018.07.024. Epub 2018 Jul 23.
Leucine-rich repeat kinase 2 (LRRK2) is the genetic cause of both familial and idiopathic Parkinson's disease (PD), and it is associated with neuronal death, vesicle trafficking, mitochondrial dysfunction, and inflammation. However, its role in secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) has not been evaluated. In this study, an ICH model was induced by injecting autologous whole blood into the right basal ganglia of adult rats. Meanwhile, primary rat cortical neurons treated with Oxyhemoglobin (OxyHb) were used as an in vitro ICH model. Protein levels of LRRK2 increased significantly in brain tissues after ICH. Upregulation of LRRK2 by genetic overexpression augmented inflammatory responses, behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, and cell death involved in SBI following ICH. Downregulation of LRRK2 by GNE7915 (a specific chemical inhibitor of LRRK2) and genetic knockdown yielded opposite effects. Additionally, inhibiting LRRK2 by GNE7915 obviously reduced OxyHb-induced neuronal apoptosis in vitro and attenuated phosphorylation of p38 MAPK and Drosha both in vivo and in vitro. Therefore, we concluded that LRRK2 participated in ICH-induced SBI by mediating inflammatory responses, behavioral and cognitive dysfunction, brain edema, and BBB injury and by modulating neuronal death and dysfunction and regulating the p38 MAPK/Drosha pathway.
富含亮氨酸重复激酶 2（LRRK2）是家族性和特发性帕金森病（PD）的遗传原因，与神经元死亡、囊泡运输、线粒体功能障碍和炎症有关。然而，它在脑出血（ICH）引起的继发性脑损伤（SBI）中的作用尚未得到评估。在这项研究中，通过将自体全血注入成年大鼠右侧基底节来诱导 ICH 模型。同时，用氧合血红蛋白（OxyHb）处理的原代大鼠皮质神经元被用作体外 ICH 模型。ICH 后，脑组织中 LRRK2 的蛋白水平显著升高。通过遗传过表达上调 LRRK2 会增强炎症反应、行为和认知功能障碍、脑水肿、血脑屏障（BBB）损伤和 SBI 中的细胞死亡。通过 GNE7915（LRRK2 的特异性化学抑制剂）下调 LRRK2 和基因敲低会产生相反的效果。此外，通过 GNE7915 抑制 LRRK2 可明显减少体外 OxyHb 诱导的神经元凋亡，并减轻体内和体外 p38 MAPK 和 Drosha 的磷酸化。因此，我们得出结论，LRRK2 通过介导炎症反应、行为和认知功能障碍、脑水肿和 BBB 损伤以及调节神经元死亡和功能障碍以及调节 p38 MAPK/Drosha 通路，参与 ICH 诱导的 SBI。
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