<scp>USP</scp>14 inhibitor attenuates cerebral ischemia/reperfusion‐induced neuronal injury in mice

Abstract

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 ( DUB s) are a large group of proteases that regulate protein degradation. The ubiquitin‐specific protease 14 ( USP 14) 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 ( IU 1), a specific small molecule inhibitor of USP 14, on mouse focal cerebral ischemic stroke‐induced neuronal injury in mice. We found that IU 1 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 IU 1‐treated mice compared to the control‐treated mice. Additionally, IU 1 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. image