Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway

Jie Cao; Yan Zhuang; Juyi Zhang; Zhuwei Zhang; Shuai Yuan; Peng Zhang; Haiying Li; Xiang Li; Haitao Shen; Zhong Wang; Gang Chen

Neurobiology of Disease (Nov 2018)

Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway

Jie Cao,
Yan Zhuang,
Juyi Zhang,
Zhuwei Zhang,
Shuai Yuan,
Peng Zhang,
Haiying Li,
Xiang Li,
Haitao Shen,
Zhong Wang,
Gang Chen

Affiliations

Jie Cao: 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
Yan Zhuang: 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
Juyi Zhang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Zhuwei Zhang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Shuai Yuan: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Peng Zhang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Haiying Li: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Xiang Li: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Haitao Shen: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China
Zhong Wang: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China; Corresponding authors at: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China.
Gang Chen: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China; Corresponding authors at: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province 215006, China.

Journal volume & issue: Vol. 119
pp. 53 – 64

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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