Hsp90β inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy

摘要

OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolved in 50 μL DMSO) 25 mg·kg-1 or STA9090(dissolved in 20 μL DMSO) 50 mg·kg-1 by oral gavage respectively.The control group received DMSO alone.Thirty minutes after oral gavage,PTZ 80 mg·kg-1 was intraperitoneal injected to induce acute seizures.The number of seizures refers to the total number of epileptic mice after PTZ application.Seizure latency was defined by the time elapsed from PTZ injection to the occurrence of the first seizure.The levels of Hsp90β,GLT-1,GFAP and 20 S proteasome β1 in the cortex and hippocampus were detected by Western blotting.RESULTS The mortality were60% for 17 AAG and 43% for STA9090,and the mortality of valproate group dropped to 20%which decreased by 33.3% compared to model group.Seizure latency of valproate group obviously prolonged compared to model group(P<0.05).But the results demonstrated that 17 AAG and STA9090 had no significant differences in seizure latency.The result of Western blotting has shown that inhibition of Hsp90β significantly reduced expressions of both membrane and cytosolic Hsp90β in the hippocampus and cortex of each group of mice.However,the expressions of GLT-1 and GFAP did not show the significant difference in the cortex and hippocampus.The expression of 20 S proteasome β1 had not been obviously changed in the cortex and hippocampus among the groups.CONCLUSION 17 AAG and STA9090 did not have anticonvulsant activity and did not increase the stability of GLT-1 by disrupting proteasome-dependent GLT-1 degradation in PTZ induced mice of absence epilepsy.