Original articles
DUAN Jingyao, WANG Jingya, NI Han, HE Dujuan, LI Yunfeng, DAI Wei
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.
