大鼠卒中后抑郁模型中NMDA受体调控NLRP3-caspase-1通路的作用及分子机制  

Role and molecular mechanism of NMDA receptors in regulating NLRP3-caspase-1 pathway in rat model of post-stroke depression

作　　者：谢瑱 郭生龙[1] 雷琦[1] 曹冰清[1] 康涛[1] 郭生龙 Xie Zhen;Guo Shenglong;Lei Qi;Cao Bingqing;Kang Tao(Department 2 of Neurology,Shaanxi Provincial People's Hospital,Xi'an,710068 China)

机构地区：[1]陕西省人民医院神经内二科

出　　处：《神经解剖学杂志》2018年第6期715-721,共7页Chinese Journal of Neuroanatomy

基　　金：陕西省社会发展科技公关项目(2014K11-03-02-07)

摘　　要：目的:阐明卒中后抑郁与炎症之间的关系,以及该过程中N-甲基-D-天冬氨酸受体(NMDAR)对于NLRP3-caspase-1通路的影响。方法:以大脑中动脉栓塞(MCAO)模型联合大鼠悬尾实验(TST)模型构建大鼠卒中后抑郁模型,按实验要求分为Control组、MCAO组,PSD组(MCAO+TST组)、PSD+D-丝氨酸干预组(MCAO+TST+D组)、PSD+氯胺酮干预组(MCAO+TST+K组)共5组。以糖水消耗实验及血清5-HT检测评估大鼠精神状态,通过ELISA、Western Blot、real-timePCR等方法检测NLRP3-caspase-1通路相关分子的变化。随后采用D-丝氨酸及氯胺酮等对NMDAR的活性进行调节,以糖水消耗实验及血清5-HT,ELISA、Western Blot、Real-time PCR等方法进一步观察对上述指标的影响。结果:与Control组相比,MCAO组中的大鼠,其血清5-HT的水平以及糖水消耗比变化不明显(P>0.5),但NLRP3-caspase-1通路出现了激活(P<0.001);MCAO+TST组中,大鼠血清的5-HT及糖水消耗比明显下降,NLRP3-caspase-1通路相关分子出现了明显活化(P<0.001);而通过应用NMDA受体共激动剂D-丝氨酸干预,在MCAO+TST+D组中,大鼠糖水消耗比及血清5-HT出现了进一步的下降,同时NLRP3-caspase-1通路相关分子的激活较前更为明显(P<0.001);而应用NMDA受体拮抗剂氯胺酮后,MCAO+TST+K组中,大鼠糖水消耗比及血清5-HT较前明显提高,同时NLRP3-caspase-1通路相关分子的激活较前出现了下调(P<0.001)。结论:NLRP3-caspase-1通路所代表的炎症反应过程与卒中后抑郁的发生发展密切相关,而通过干预与其密切相关的NMDA受体,可实现对该过程的调控,起到影响卒中后抑郁程度的作用。Objective: To elucidate the relationship between post-stroke depression and inflammation,and the effect of NMDA receptor on NLRP3-caspase-1 pathway in this process.Methods: A rat model of post-stroke depression was established by using the middle cerebral artery occlusion ( MCAO) model combined with the tail suspension test ( TST) model.According to the experimental requirements,aninrals were divided into 5 groups as follows: Control group,MCAO group, post-stroke depression ( PSD) group ( MCAO + TST group) ,PSD and D-serine intervention group ( MCAO + TST + D group) ,PSD and ketamine intervention group ( MCAO + TST + K group) .The mental state of rats was evaluated by saccharide consumption test and serum 5-HT assay.The changes of NLRP3-caspase-1 pathway-related molecules were detected by ELISA,Western Blot and real-time PCR.Subsequently,the activity of NMDA receptors was perturbed with D-serine and ketamine to observe changes in the mental state of rats assessed by using saccharide consumption test and serum 5-HT assay,and changes in molecules related to NLRP3-caspase-1 pathway by using ELISA,Western Blot and Real- time PCR.Results: Compared with the control group,there was no obvious change in the 5-HT and sugar consumption ratios in the MCAO group ( P>0.05) ,but the NLRP3-caspase-1 pathway was activated ( P<0.001) .In the MCAO + TST group,the serum 5-HT and sugar consumption ratios of the mouse decreased significantly,and the NLRP3-caspase- 1 pathway-related molecules showed significant activation ( P<0.001) .By using the NMDA receptor co-agonist D-serine in the MCAO + TST + D group,the sugar consumption ratio and serum 5-HT showed further decrease than before,and the activation of NLRP3-caspase-1 pathway-related molecules was more obvious than before ( P<0.001) .By using the NMDA receptor antagonist ketamine in the MCAO + TST + K group,the sugar consumption ratio and serum 5-HT of the rats were significantly higher than before,and the activation of NLRP3-caspase-1 pathway-related molecules was down-regulated

关 键 词：卒中后抑郁 NMDAR NLRP3 CASPASE-1 IL-1β 大鼠 

分 类 号：R743.3[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]