Investigation Of The Role Of Ubiquitin-Specific Protease USP25 In Stroke

Stroke,as an acute vascular event with extremely high disability and mortality worldwide,is often accompanied with massive neuronal death surrounding the infarct lesion,a severe inflammatory response and the collapse of the Blood Brain Barrier(BBB).These events work together to cause irreversible brain damage in patients and heavy burden on their families and the society.Since there is no effective prevention and treatment for now,it is imperative to identify novel and effective drug targets.Ubiquitin-Specific Protease 25(USP25)is a deubiquitinase which belongs to the USP family.In this project,we carried out our research work using both genetic and pharmacological strategies.We took advantage of a model of global cerebral ischemia(Bilateral Common Carotid Artery Occlusion,BCAO),and found that Usp25 knockout mice displayed better motor and cognitive function compared to WT mice in behavioral tests.In addition,Usp25 deficiency markedly attenuated gliosis in the hippocampus and reduced the expression of pro-apoptotic Caspase 3,pro-inflammatory cytokines interleukin 1β(IL-1β)and tumor necrosis factor(TNF).Moreover,we administered Middle Cerebral Artery Occlusion(MCAO)mice with USP25 inhibitor AZ2,and found that AZ2 significantly improved the motor coordination ability of MCAO mice,and suppressed gliosis in the mouse brains after ischemia-reperfusion.In summary,our study illustrates that genetic ablation and phamarcological inhibition of USP25 restored motor coordination and reversed cognitive deficits in stroke mouse models by inhibiting glia-mediated neuroinflammation.Our research reveals a novel mechanism underlying neuroinflammation in stroke,and a potential drug target for the treatment of stroke.