Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway.
Neurobiol Dis
; 119: 53-64, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-30048803
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Lesões Encefálicas
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Transdução de Sinais
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Hemorragia Cerebral
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Ribonuclease III
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Proteínas Quinases p38 Ativadas por Mitógeno
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Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Limite:
Animals
Idioma:
En
Revista:
Neurobiol Dis
Ano de publicação:
2018
Tipo de documento:
Article