title: USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice.
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.
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Min
authors.affiliation: Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology and Institute of Stomatological Research, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.|Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Lanhai
authors.initials: L
authors.lastname: Lü
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Freeling
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Doug S
authors.initials: DS
authors.lastname: Martin
authors.affiliation: Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002545:Brain Ischemia / Q000188:drug therapy* / Q000523:psychology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use*; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000523:psychology; D016019:Survival Analysis; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors*
chemical_list: C000594744:1-(1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl)-2-pyrrolidin-1-ylethanone; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D011758:Pyrroles; D011759:Pyrrolidines; C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: IU1; USP14; deubiquitinating enzymes; ischemia; small molecule inhibitor; stroke