倍他司汀抑制抗精神病药所致星形胶质细胞焦亡初探  

Preliminary exploration of betahistine in inhibiting antipsychotic-induced pyroptosis in astrocytes

作　　者：段燈 葛笑妹 陈佳 周如琴 李素玉 何梦 DUAN Deng;GE Xiaomei;CHEN Jia;ZHOU Ruqin;LI Suyu;HE Meng(School of Chemistry,Chemical Engineering and Life Sciences,Wuhan University of Technology,Hubei Wuhan 430070,China;Wuhan Seventh Hospital Zhongnan Road Street No.1 Community Health Service Center,Hubei Wuhan 430070,China)

机构地区：[1]武汉理工大学化学化工与生命科学学院,湖北武汉430070 [2]武汉市第七医院中南路街第一社区卫生服务中心,湖北武汉430070

出　　处：《中国医院药学杂志》2025年第7期729-737,共9页Chinese Journal of Hospital Pharmacy

基　　金：湖北省基金面上项目(编号:2021CFB301)。

摘　　要：目的:探讨抗精神病药物(antipsychotics,APs)诱导星形胶质细胞死亡的机制及干预策略。方法:体外培养人源星形胶质细胞,分别用10μmol·L^(-1)奥氮平(olanzapine,OLZ)或喹硫平(quetiapine,QUE)与不同浓度的倍他司汀(10μmol·L^(-1)或5μmol·L^(-1))联合处理24 h。通过实时荧光定量PCR、蛋白质免疫印迹法、免疫荧光和电镜观察,评估OLZ或QUE对细胞焦亡的激活作用以及倍他司汀的抑制效果。结果:与对照组相比,OLZ或QUE处理显著上调细胞焦亡经典途径标志蛋白Caspase-1、GSDMD、NLRP3和IL-1β以及非经典途径标志蛋白Caspase-4和Caspase-5的mRNA及蛋白表达(均为P<0.05)。倍他司汀联合处理呈剂量依赖性抑制上述焦亡标志蛋白的mRNA及蛋白表达上调(均为P<0.05)。细胞形态学研究进一步显示,OLZ或QUE处理组细胞膜出现明显的焦亡样孔洞,而倍他司汀联合处理后孔洞数量显著减少,接近对照组水平。结论:OLZ和QUE通过激活依赖Caspase-1的经典焦亡途径和依赖Caspase-4/5的非经典焦亡途径,诱导星形胶质细胞焦亡。倍他司汀可同时抑制这两种途径的激活,减少膜孔形成,从而抑制OLZ和QUE诱导的星形胶质细胞焦亡,发挥脑保护作用。OBJECTIVE To explore the mechanisms underlying antipsychotics(APs)in inducing astrocyte death and the potential intervention strategies.METHODS Human-derived astrocytes were cultured in vitro and treated with 10μmol·L^(-1)olanzapine(OLZ)or quetiapine(QUE)combined with betahistine at different concentrations(10μmol·L^(-1)or 5μmol·L^(-1))for 24 hours.Quantitative real-time PCR,Western blot,immunofluorescence and electron microscopy were used to assess the activation of pyroptosis by OLZ and QUE,as well as the inhibitory effects of betahistine.RESULTS Compared to the control group,OLZ or QUE treatment significantly upregulated mRNA and protein expression levels of key markers in the classical pyroptosis signaling pathway,including Caspase-1,gasdermin D(GSDMD),NOD-like receptor thermal protein domain associated protein 3(NLRP3),interleukin-1beta(IL-1β),as well as Caspase-4 and Caspase-5 involved in the non-classical signaling pathway in astrocytes(all P<0.05).Co-treatment of betahistine and OLZ/QUE significantly inhibited the upregulation of mRNA and protein expressions of these pyroptosis-related markers in a dose-dependent manner(all P<0.05).Further morphological studies revealed that OLZ or QUE treatment significantly induced pyroptosis-like membrane perforations in astrocytes,while cotreatment of betahistine and OLZ/QUE reduced the number of membrane perforations,with cell morphology resembling that of the control group.CONCLUSION OLZ or QUE induces astrocytic pyroptosis through activating both classical Caspase-1-dependent and non-classical Caspase-4/5-dependent pyroptosis signaling pathways.Betahistine inhibits the activation of these pathways,thus reducing pore formation and thereby mitigating OLZ/QUE-induced astrocytic pyroptosis,and providing a neuroprotective effect.

关 键 词：奥氮平 喹硫平 倍他司汀 细胞焦亡 NLRP3 

分 类 号：R964[医药卫生—药理学]