枸橼酸坦度螺酮组合物通过抑制神经元氧化损伤和调节小胶质细胞活化发挥抗抑郁作用  

Tandospirone citrate composition exerts antidepressant effects by inhibiting neuronal oxidative damage and microglial activation

作　　者：邓岚 曾娟 王征琴 唐新新 陈刚 吴建明 吴安国 DENG Lan;ZENG Juan;WANG Zhengqin;TANG Xinxin;CHEN Gang;WU Jianming;WU Anguo(School of Pharmacy,Southwest Medical Univisity,Luzhou 646000,China;Sichuan Credit Pharmaceutical CO.,Ltd.,Luzhou 646000,China)

机构地区：[1]西南医科大学药学院,泸州646000 [2]四川科瑞德制药股份有限公司,泸州646000

出　　处：《西南医科大学学报》2024年第2期166-171,共6页Journal of Southwest Medical University

基　　金：国家自然科学基金青年项目(81903829)。

摘　　要：目的筛选不同组成的枸橼酸坦度螺酮组合物(tandospirone citrate compositions,TCCs),以评估其改善小鼠抑郁症行为的效果,并探究枸橼酸坦度螺酮的神经保护作用。方法采用动物行为实验和体外细胞实验的方法。在动物实验中,通过强迫游泳测试(forced swim-ming test,FST)和尾悬挂测试(tail suspension test,TST),评估五种TCCs对小鼠抑郁样行为的影响。在体外细胞实验中,研究表现最佳的组合物TCC-4在抑制过氧化氢(hydrogen peroxide,H_(2)O_(2))诱导的PC-12细胞损伤和脂多糖(lipopolysaccharide,LPS)诱导的BV-2细胞神经炎症的作用。结果在FST和TST实验中,TCCs显著减少了小鼠的不动时间(P<0.05),显示出其抗抑郁样效果。体外细胞实验中发现,表现最佳的TCC-4能有效抑制H_(2)O_(2)诱导的PC-12细胞死亡、活性氧(reactive oxygen species,ROS)的产生及线粒体膜电位(mitochondrial membrane po-tential,MMP)的降低(P<0.001),且减轻了LPS诱导的BV-2细胞激活和吞噬作用(P<0.001)。结论TCCs,尤其是TCC-4,显示出良好的抗抑郁效果。其作用机制可能与抑制神经元的氧化损伤和调节小胶质细胞的活化有关。这些发现为TCC-4作为新型抗抑郁药物的潜力提供了支持,并为其在临床应用的进一步研究奠定了理论基础。Objective Different tandospirone citrate compositions(TCCs)were screened to assess their effectiveness in improv-ing depressive behaviors in mice and to explore the neuroprotective effects of the most effective combinations.Methods Animal behav-ioral experiments and in vitro cellular experiments were used.In animal experiments,the effects of five TCCs on depression-like behav-iors in mice were evaluated by the forced swim test(FST)and tail suspension test(TST).In vitro experiments were conducted to inves-tigate the effects of TCC-4,which exhibited the best performance,on inhibiting hydrogen peroxide(H_(2)O_(2))-induced damage in PC-12 cells and lipopolysaccharide(LPS)-induced neuroinflammation in BV-2 cells.Results In FST and TST experiments,TCCs signifi-cantly reduced the resting time of mice(P<0.05),showing their antidepressant-like effects.In H_(2)O_(2)-induced PC-12 cells,the best-performing TCC-4 was found to effectively inhibit cell death,reactive oxygen species(ROS)production,and mitochondrial membrane potential(MMP)reduction(P<0.001).Additionally,TCC-4 could attenuate LPS-induced BV-2 cell activation and phagocytosis(P<0.001).Conclusion TCCs,especially TCC-4,showed favorable antidepressant effects.The mechanism of action might be related to the inhibition of oxidative damage in neurons and the regulation of microglia activation.These findings provided support for the potential of TCC-4 as a novel antidepressant drug and laid the foundation for further studies on its clinical application.

关 键 词：抑郁症 枸橼酸坦度螺酮组合物 氧化应激 神经炎症 小胶质细胞 

分 类 号：R964[医药卫生—药理学]