Sigma-1受体在YL-0919快速抗PTSD效应中的作用及机制研究OA

Objective To investigate the effects and possible mechanisms of YL-0919(a novel class 1.1 antidepressant drug with an original chemical structure,independently developed by our research institute)in the treatment of post-traumatic stress disorder(PTSD)and cognitive impairment in a mouse model of inescapable footshock(IFS).Methods Highly selective sigma-1 receptor antagonist BD-1047 was intraperitoneally injected to verify the target of YL-0919:(1)Mice were randomly divided into the control group,IFS+vehiclegroup,IFS+YL-0919(2.5 mg/kg)+vehicle group,and IFS+YL-0919+BD-1047(2.0 or 4.0 mg/kg)groups.The plantar surface of the mice was subjected to two consecutive days of electric shockto establish an IFS model.Mice in the IFS+YL-0919+vehicle group and the IFS+YL-0919+BD-1047 group were orally administeredwith YL-0919(2.5 mg/kg)twice daily while those in theBD-1047 group(2.0 or 4.0 mg/kg)were administered intraperitoneally once daily,starting two days before YL-0919 administration.One hour after drug administration on the seventh day,the rapid anti-PTSD effect of YL-0919 was evaluated via behavioral experiments.(2)Fluoxetine(Flx)was used as a positive control drug.Mice were randomly divided into the control group,IFS+vehicle group,IFS+YL-0919(2.5 mg/kg)+vehicle group,IFS+YL-0919+BD-1047(2.0 mg/kg)group,and IFS+Flx(10.0 mg/kg)+vehicle group.Twenty-four hours after drug administration on the fifth day,the rapid anti-PTSD effect of YL-0919 was assessed via behavioral experiments.(3)Western blot was used to detect the expression levels of synaptic plasticity protein PSD95,AMPA-type glutamate receptor subunit-1(GluA1),and brain-derived neurotrophic factor(BDNF)in the prefrontal cortex of mice.Results(1)Compared with the control group,there was an increase in freezing time and asignificant decrease in recognition indexes in the IFS model group(P<0.05).Compared with the IFS group,these changes were significantly reversed by YL-0919(2.5 mg/kg)(P<0.05).In contrast,Flx(10.0 mg/kg)did not mitigate the behavior after 5 days of continuous administration,but14 days of administration of Flx(10.0 mg/kg)showed a significant anti-PTSD effect but failed to significantly improve cognitive deficits in the IFS model mice,suggesting that YL-0919 could exert rapid anti-PTSD effect and improve cognitive function compared to Flx.Compared with the IFS+YL-0919+vehicle group,the anti-PTSD and pro-cognitive effects of YL-0919 were blocked by BD-1047(2.0 or 4.0 mg/kg).(2)Compared with the control group,the expression levels of PSD95,BDNF,and GluA1 proteins in the prefrontal cortex of mice were significantly reduced in the IFS model group(P<0.05),but were significantly increased in the IFS+YL-0919(2.5 mg/kg,administration for 5 days)group compared with the IFS model group(P<0.05).Compared with the IFS+YL-0919+vehicle group,the increased expression levels of PSD95,BDNF,and GluA1 proteins induced by YL-0919 were blocked after BD-1047(2.0 mg/kg)administration.Compared with the IFS model group,the expression levels of PSD95,BDNF,and GluA1 proteins in the prefrontal cortex of mice in the IFS+Flx(10 mg/kg,administration for 5 days)group did not change significantly.Conclusion YL-0919 can exert rapid anti-PTSD effects and relieve cognitive impairment in the IFS model,and the mechanism of the action may be related to the activation of sigma-1 receptors to regulate synaptic plasticity and BDNF expression in the prefrontal cortex.