青蒿琥酯调节cGAS-STING信号通路对抑郁症模型小鼠神经炎性反应的影响  

Effect of artesunate on neuroinflammation in depressed mouse model by regulating cGAS-STING signaling pathway

作　　者：高超[1] 张润菡 王伟[2] 赵曼婷 焦艳[3] 李喆[3] GAO Chao;ZHANG Runhan;WANG Wei;ZHAO Manting;JIAO Yan;LI Zhe(Department of Child Health,Cangzhou Central Hospital,Cangzhou 061000;Department of Emergency Medicine,Cangzhou Central Hospital,Cangzhou 061000;Department of Pharmacy,Cangzhou Medical College,Cangzhou 061000,China)

机构地区：[1]沧州市中心医院儿童保健科,河北沧州061000 [2]沧州市中心医院急诊医学部,河北沧州061000 [3]沧州医学高等专科学校药学系,河北沧州061000

出　　处：《基础医学与临床》2024年第8期1126-1132,共7页Basic and Clinical Medicine

基　　金：沧州市重点研发计划指导项目(222106097)。

摘　　要：目的探讨青蒿琥酯(ART)调节环磷酸鸟苷-腺苷酸合成酶(cGAS)-干扰素基因刺激因子(STING)通路对抑郁症小鼠神经炎性反应的影响。方法小鼠分为模型组、对照组、ART低剂量组、ART高剂量组、氟西汀组、ART高剂量+RocA(cGAS-STING通路激活剂)组。糖水消耗实验、强迫游泳实验评估小鼠的抑郁行为;HE染色检测海马组织病理变化;ELISA检测白细胞介素(IL)-6、肿瘤坏死因子-α(TNF-α)、五羟色胺(5-HT)、多巴胺(DA)水平;TUNEL染色检测神经元凋亡;Western blot检测Bcl-2相关X蛋白(Bax)、p53、cGAS、STING蛋白。结果与对照组相比,模型组小鼠表现出神经元性脓疱变性,糖水消耗率、5-HT、DA水平降低,强迫游泳静止时间延长,IL-6、TNF-α水平、神经元凋亡率及Bax、p53、cGAS、STING蛋白表达升高(P<0.05);与模型组相比,ART低剂量组、ART高剂量组、氟西汀组小鼠海马神经元损伤有所缓解,糖水消耗率、5-HT、DA水平升高,强迫游泳静止时间缩短,IL-6、TNF-α水平、神经元凋亡率及Bax、p53、cGAS、STING蛋白表达降低(P<0.05);RocA逆转了高剂量ART对小鼠抑郁症的改善作用。结论ART抑制抑郁症小鼠神经炎性反应及神经元凋亡,上调胺类神经递质水平的机制可能与阻断cGAS-STING通路有关。Objective To investigate the effect of artesunate(ART)on neuroinflammation in depressed mice by regulating the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon gene(STING)pathway.Methods Mice were divided into model group,control group,low-dose ART group,high-dose ART group,fluoxetine group,and high-dose ART+RocA(cGAS-STING pathway activator)group.Sugar solution consumption experiment and forced swimming experiment were applied to evaluate the depressive behavior of mice;HE staining microscopy was applied to detect pathological changes in hippocampal tissue;ELISA method was applied to detect the level of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),serotonin(5-HT)and dopamine(DA);TUNEL staining microscopy was applied to detect neuronal apoptosis;Western blot was applied to detect Bcl-2 associated X protein(Bax),p53,cGAS,and STING proteins.Results Compared to the control group,the mice in the model group exhibited neuronal pustule degeneration,the sugar water consumption rate,level of 5-HT and DA decreased,the rest time of forced swimming increased.The level of IL-6 and TNF-α,neuronal apoptosis rate,expression of Bax,p53,cGAS,and STING proteins all elevated(P<0.05);Compared with model group,the damage to hippocampus neurons in the ART low-dose group,ART high-dose group and fluoxetine group neuronal pustular degeneration was alleviated,while sugar water consumption rate,5-HT,and DA levels increased,the rest time of forced swimming reduced,the level of IL-6 and TNF-α,neuronal apoptosis rate and the expression of Bax,p53,cGAS,and STING proteins reduced(P<0.05);RocA reversed the improvement effect of high-dose ART on depression in mice.Conclusions ART inhibits neuroinflammation and neuronal apoptosis in depressed mice,and up-regulates amine neurotransmitters expression.The mechanism is potentially related to the blocking of cGAS-STING pathway.

关 键 词：青蒿琥酯 环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子通路 抑郁症 炎性反应 凋亡 

分 类 号：R285.5[医药卫生—中药学]