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Adenosine A2A receptor antagonist KW6002 protects against A53T mutant alpha-synuclein-induced brain damage and neuronal apoptosis in Parkinson's disease mice by restoring autophagic flux.
Hu, Qidi; Xu, Lingli; Liu, Xiaotian; Wang, Yuwen; Yuan, Jianshu.
Afiliación
  • Hu Q; Department of Ophthalmology, Wenzhou Medical University Ningbo Eye Hospital, Ningbo 315040, China; Ningbo Clinical Medical Research Center for Ophthalmology, Ningbo 315040, China. Electronic address: huqidi2007@sina.com.
  • Xu L; Department of Ophthalmology, Wenzhou Medical University Ningbo Eye Hospital, Ningbo 315040, China.
  • Liu X; Department of Ophthalmology, Wenzhou Medical University Ningbo Eye Hospital, Ningbo 315040, China.
  • Wang Y; Department of Ophthalmology, Wenzhou Medical University Ningbo Eye Hospital, Ningbo 315040, China.
  • Yuan J; Department of Ophthalmology, Wenzhou Medical University Ningbo Eye Hospital, Ningbo 315040, China.
Neurosci Lett ; 826: 137610, 2024 Mar 15.
Article en En | MEDLINE | ID: mdl-38157926
ABSTRACT

BACKGROUND:

Protein misfolding and inclusion body aggregation caused by α-Syn mutations in the brain often cause neurodegeneration and cognitive impairment, among which the A53T point mutation is more common. Inhibition of adenosine A2A receptor (A2AR) can alleviate the pathological symptoms of brain dysfunction caused by A53T-α-Syn protofibrils, but the mechanism of action is still unclear.

AIM:

This studies aimed to investigate the potential therapeutic role of the A2AR inhibitor KW6002 in a mouse model of brain synucleinopathy.

METHODS:

A53T-α-Syn fibre precursor cell nuclear protein was injected into the bilateral prefrontal cortex of mice to establish a synucleinopathy animal model, and the A2AR inhibitor KW6002 (5 mg/kg) was injected intraperitoneally to intervene.

RESULT:

The intracerebral injection of A53T-α-Syn protofibrils triggers the formation of inclusion bodies in the brain, leading to astrocyte activation, an increased number of apoptotic cells, and suppression of autophagic flux. The administration of KW6002 significantly reversed these phenomena. In vitro experiments revealed that A53T-α-Syn protofibrils inhibited HT-22 autophagy in mouse hippocampal neuronal cells, whereas KW6002 increased cellular autophagic flux, upregulated the expression of LAMP2A and Hsc70 proteins and inhibited the expression of SQSTM1 protein. The present study suggests that KW6002 reduces the level of α-Syn phosphorylation by inhibiting A2AR protein, at the same time, enhances the autophagic flux of neuronal cells, resulting in the degradation of A53T-α-Syn protofibrils and thus reducing the neuronal toxicity and apoptosis induced by A53T-α-Syn protofibrils.

CONCLUSION:

KW6002 has a significant protective effect on neuronal injury induced by A53T-α-Syn.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Purinas / Lesiones Encefálicas Límite: Animals Idioma: En Revista: Neurosci Lett Año: 2024 Tipo del documento: Article Pais de publicación: Irlanda
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Purinas / Lesiones Encefálicas Límite: Animals Idioma: En Revista: Neurosci Lett Año: 2024 Tipo del documento: Article Pais de publicación: Irlanda