TSPO介导YL-IPA08抗创伤后应激障碍作用的药理学研究

Translocator protein mediated anti-PTSD effects of YL-IPA08

目的利用基因敲除动物研究18ku转位蛋白(TSPO)在YL-IPA08抗创伤后应激障碍(PTSD)中的作用并探讨其潜在药理学靶标价值。方法采用PCR法对TSPO野生型(WT)和敲除型(KO)小鼠进行基因分型鉴定。采用公认的小鼠足底电击PTSD模型,以开场实验评价小鼠自发活动,以僵住时间检测评价小鼠PTSD样恐惧行为。结果基因型鉴定证实,与TSPO WT小鼠相比,TSPO KO小鼠不含完整可表达的TSPO基因,且TSPO敲除不影响小鼠的自发活动。PTSD模型建立(第-1天~第0天)后第1、5、16天,模型组小鼠的僵住时间显著增加,TSPO敲除不影响模型小鼠的这一改变;模型建立后连续8 d(第0天~第7天)灌胃给予TSPO选择性激活剂YL-IPA08(0.3 mg/kg,1次/d)或阳性药舍曲林(15 mg/kg,1次/d)可显著降低WT模型小鼠的僵住时间,表现出显著的抗PTSD作用,而在KO小鼠上无此作用。结论首次发现TSPO WT与KO小鼠在PTSD模型中表现出相同的敏感性(即PTSD样行为表型相同),但TSPO介导了YL-IPA08的抗PTSD作用。该研究为TSPO的潜在药理学靶标价值提供了直接证据。

Objective To explore the role of 18 ku translocator protein（ TSPO） in the anti-post-traumatic-stressdisorder（ PTSD） effects of YL-IPA08 and the value of TSPO as a potential pharmacological target using gene knock out mice. Methods The PCR method was used to genotype TSPO wild type（ WT） mice and knock out（ KO） mice. Foot shock was used to establish a well-accepted mouse model of PTSD,the open field test（ OFT） was used to evaluate the locomotor activity in mice,and freezing measurement was used to evaluate the PTSD-like fear behavior in mice. Results Compared with TSPO WT mice,KO mice had no expressible TSPO gene,but showed similar locomotor activity to WT mice after PTSD modeling. On day 1,day 5 and day 16 after PTSD modeling（ day-1-day 0）,both WT and KO mice showed significant PTSD-like behavior with enhanced freezing time. However,8 d treatment（ day 0-day 7） of YL-IPA08（ 0. 3 mg/kg,once daily） or positive drug sertraline（ 15 mg/kg,once daily） after PTSD modeling significantly reduced freezing time selectively in WT mice,but not in KO mice. Conclusion It has been found for the first time that TSPO WT and KO mice can show the same sensitivity to PTSD modeling（ namely the same PTSD-like behavior performance）. Interestingly,TSPO can mediate the anti-PTSD effects of YL-IPA08. Therefore,the present study provides direct evidence for the value of TSPO as an potential pharmacological target for PTSD.