USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice.
J Neurochem
; 140(5): 826-833, 2017 03.
Article
em En
| MEDLINE
| ID: mdl-28029679
ABSTRACT
Stroke is associated with over-production of misfolded and aggregating proteins. However, it remains largely unclear whether enhanced removal of protein aggregates following ischemic stroke is neuroprotective. Deubiquitinating enzymes (DUBs) are a large group of proteases that regulate protein degradation. The ubiquitin-specific protease 14 (USP14) is a DUB that is associated with the proteasome and negatively regulates proteasome activity. In this study, we examined the effect of 1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone (IU1), a specific small molecule inhibitor of USP14, on mouse focal cerebral ischemic stroke-induced neuronal injury in mice. We found that IU1 treatment attenuated ischemic stroke-caused neuronal injury, which was reflected by increased survival rate, reduced infarct volume, as well as decreased neuronal loss in the IU1-treated mice compared to the control-treated mice. Additionally, IU1 treatment is associated with reduced protein aggregates and enhanced proteasome functionality. These data not only highlight the significance of protein homeostasis in cerebral ischemia/reperfusion-induced neuronal injury but also extend the therapeutic role of DUB inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
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Pirróis
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Pirrolidinas
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Traumatismo por Reperfusão
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Isquemia Encefálica
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Fármacos Neuroprotetores
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Ubiquitina Tiolesterase
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Neurônios
Limite:
Animals
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos