18kDa转位蛋白选择性配体YL-IPA08抗创伤后应激障碍作用

Anti-post-traumatic-stress-disorder effects of YL-IPA08,a selective 18kDa translocator protein ligand

目的研究18k Da转位蛋白(TSPO)选择性配体化合物YL-IPA08抗创伤后应激障碍(PTSD)作用。方法采用时间依赖性敏化应激(TDS)法建立大鼠PTSD模型,采用开场实验评价大鼠自发活动;采用僵住时间测定、高架十字迷宫实验和新物体识别实验评价大鼠PTSD样行为;采用ELISA法检测大鼠海马四氢孕酮含量变化。结果与对照组相比,PTSD模型处理及药物处理均不影响大鼠自发活动(P>0.05),但PTSD模型组大鼠呈现出显著的PTSD样行为,表现为僵住时间延长、高架十字迷宫实验中进入开臂的时间和次数百分比降低,新物体识别实验中物体识别指数下降(P<0.05或0.01),同时模型组大鼠海马内四氢孕酮含量降低(P<0.05),模型建立后开始灌胃给予YL-IPA08(0.05~0.1 mg/kg)或阳性药舍曲林(15 mg/kg)显著逆转上述系列PTSD样行为学改变(P<0.05或0.01),并显著增加模型大鼠海马四氢孕酮水平。结论 TSPO选择性配体YL-IPA08能够改善大鼠PTSD样行为,其作用机制与升高海马四氢孕酮含量有关。

Objective To explore the anti-post-traumatic-stress-disorder（anti-PTSD）effects of YL-IPA08,a selective 18 k Da translocator protein（TSPO）ligand. Methods The time-dependent stress sensitization（TDS）method was used to establish a rat model of PTSD. The open field test（OFT）was used to evaluate the locomotor activity in rats. The contextual freezing（CF）measurement,elevated plus maze（EPM）test and novel objective recognition（NOR）test were used to evaluate the PTSD-like behaviors in rats. The concentration of allopregnanolone in rat hippocampus was detected by ELISA. Results Compared with the control group,neither TDS nor drug treatment affected the locomotor activity in rats（P〉0.05）. However,PTSD rats showed significant PTSD-like behaviors with enhanced CF time in CF mearsurement,decreased open arm time and open arm entries in EPM test,and dropped object recognition index in NOR test（P〈0.05 or 0.01）. Moreover,the concentration of hippocampus allopregnanolone was decreased in PTSD rats（P〈0.05）. YL-IPA08（0.05-0.1 mg/kg）or positive drug sertraline（15 mg/kg）,administered intragastrically after establishment of PTSD model,significantly reversed the above PTSD-like behavioral changes（P〈0.05 or 0.01）and increased the concentration of hippocampus allopregnanolone in PTSD rats. Conclusion YL-IPA08 could improve the PTSD-like behavior in rats,and the mechanism may be related to the increased allopregnanolone level in hippocampus.