摘要
目的探讨紫草素调节环磷酸鸟苷-腺苷酸合成酶(cGAS)-干扰素基因刺激因子(STING)信号通路对脓毒症相关性脑病(SAE)大鼠神经炎症的影响及可能机制。方法将大鼠随机分为SAE组,紫草素低、中、高剂量组(1.33、2.66、5.32 mg/kg),紫草素高剂量+Roc A组(5.32 mg/kg紫草素+0.67 mg/kg cGAS-STING信号通路激活剂Roc A)和对照组,每组12只。除对照组外,其余各组大鼠均构建SAE模型,造模成功后开始给药,每天1次,持续14 d。给药结束后,通过Y迷宫实验、旷场实验分别评估大鼠的学习记忆能力、焦虑状态;观察其海马齿状回(DG)区神经元的病理变化;检测其海马DG区脑组织中CD86、CD206阳性细胞数以及白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)、IL-4、IL-10水平和cGAS、STING蛋白表达水平。结果与SAE组相比,紫草素低、中、高剂量组大鼠神经元损伤得到改善,“新臂”内活动距离百分比、中心区域停留时间、行走距离以及海马DG区脑组织中完整神经元数目、CD206阳性细胞数和IL-4、IL-10水平均显著增加/升高/延长(P<0.05),海马DG区脑组织中CD86阳性细胞数以及IL-1β、TNF-α水平和cGAS、STING蛋白表达均显著减少/降低/下调(P<0.05),且紫草素的作用呈剂量依赖性(P<0.05)。Roc A可显著逆转高剂量紫草素对SAE大鼠神经炎症的改善作用(P<0.05)。结论紫草素可能通过抑制cGAS-STING信号通路活性来改善SAE大鼠神经炎症。
OBJECTIVE To investigate the effect and possible mechanism of shikonin on neuroinflammation in sepsisassociated encephalopathy(SAE)rats by regulating the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon gene(STING)signaling pathway.METHODS Rats were randomly separated into SAE group,shikonin low-dose,medium-dose and high-dose groups(1.33,2.66,5.32 mg/kg),high dose of shikonin+Roc A group(5.32 mg/kg shikonin+0.67 mg/kg cGAS-STING signaling pathway activator Roc A),and control group,with 12 rats in each group.Except for the control group,SAE models were constructed in all other groups.After successful modeling,administration began once a day for 14 days.After administration,the Y-maze experiment and open-field experiment were applied to evaluate the learning and memory ability and anxiety state of rats,respectively.The pathological changes of neurons in the dentate gyrus(DG)of the hippocampus were observed.The number of CD86 and CD206 positive cells,the levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),IL-4 and IL-10,and the protein expressions of cGAS and STING were detected in the brain tissue of the hippocampus DG region.RESULTS Compared with the SAE group,the neuronal damage of rats in shikonin low-dose,medium-dose and high-dose groups were improved;the percentage of activity distance in the“new arm”,the duration of stay in the central area,walking distance,the number of intact neurons and CD206 positive cells in the brain tissue of the hippocampal DG area,and the levels of IL-4 and IL-10 increased/rised/prolonged significantly(P<0.05);the number of CD86 positive cells in the brain tissue of the hippocampal DG region,the levels of IL-1βand TNF-α,and protein expressions of cGAS and STING were significantly reduced/decreased/down-regulated(P<0.05),and the effect of shikonin was dose-dependent(P<0.05).Roc A could significantly reverse the improvement effect of high-dose shikonin on neuroinflammation in SAE rats(P<0.05).CONCLUSIONS Shikonin can improve neuroinflammation in SAE rats by inhibiting cGAS-STING signaling pathway.
作者
冯大磊
王兆
杨颖颖
杨蕾
FENG Dalei;WANG Zhao;YANG Yingying;YANG Lei(Dept.of Critical Care Medicine,the First People’s Hospital of Zunyi,Guizhou Zunyi 563000,China;Dept.of Oncology,the First People’s Hospital of Zunyi,Guizhou Zunyi 563000,China;Dept.of Pediatric Intensive Care Medicine,the First People’s Hospital of Zunyi,Guizhou Zunyi 563000,China)
出处
《中国药房》
CAS
北大核心
2024年第21期2640-2645,共6页
China Pharmacy
基金
合肥市第一人民医院研究与试验发展项目(No.院科字〔2020〕13号)。
