目的 探讨雷公藤甲素通过上调miR-137调控小胶质细胞极化改善抑郁症的作用及潜在分子机制。方法 50只SD大鼠随机分为对照组、模型组、雷公藤甲素组、雷公藤甲素＋NC抑制剂组和雷公藤甲素＋miR-137抑制剂组，每组10只。通过构建慢性不可预知性应激（CUS）抑郁大鼠模型，采用糖水偏好实验、强迫游泳实验和悬尾实验检测大鼠的行为学变化，实时定量聚合酶链反应（RT-qPCR）检测大鼠海马中miR-137的表达水平，Western blotting分别检测大鼠海马组织中离子钙接头蛋白分子-1（Iba-1）、诱导型一氧化氮合酶（iNOS）和精氨酸酶1（Arg1）蛋白表达，ELISA法检测大鼠海马中神经递质5-羟色胺（5-HT）和多巴胺（DA）水平以及炎性因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、白细胞介素-4（IL-4）、白细胞介素-10（IL-10）的水平。结果 与对照组比较，模型组大鼠糖水偏好百分比显著降低，不动时间显著增加，体质量明显下降，海马中miR-137表达显著降低，Iba-1和iNOS蛋白以及IL-1β和IL-6水平显著增加，Arg1蛋白、5-HT、DA、IL-4和IL-10水平显著降低（P<0.05）。与模型组比较，雷公藤甲素显著减轻大鼠的抑郁样行为，上调miR-137表达，降低海马组织中Iba-1和iNOS蛋白水平以及抑制IL-1β和IL-6水平，升高Arg1蛋白表达以及5-HT、DA、IL-4和IL-10水平（P<0.05）。miR-137抑制剂处理后显著逆转了雷公藤甲素对小胶质细胞活化的抑制作用。结论 雷公藤甲素通过上调miR-137改善CUS诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。

Objective To explore the role and potential molecular mechanism of triptolide in regulating microglial polarization through miR-137 in depression. Methods 50 SD rats were randomly divided into control group, model group, triptolide group, triptolide + NC inhibitor group and triptolide + miR-137 inhibitor group, and 10 rats in each group. The rat model of depression induced by chronic unpredictable stress (CUS) was established. The behavioral changes of rats were detected by sugar water preference test, forced swimming test and tail suspension test, and the expression of miR-137 in hippocampus was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Western bloting was used to detect the expression of ionized calcium junction protein-1 (Iba-1), inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1) in rat hippocampus. The levels of neurotransmitters 5-hydroxytryptamine (5-HT) and dopamine (DA) and the contents of inflammatory factors such as IL-1β, IL-6, IL-4 and IL-10 in the hippocampus of rats were measured by ELISA method. Results Compared with the control group, the percentage of sugar preference in the model group was significantly decreased, the immobility time was significantly increased, the body weight was significantly decreased, the expression of miR-137 in the hippocampus was significantly decreased, the levels of Iba-1 and iNOS protein and IL-1β and IL-6 were significantly increased, and the levels of Arg1 protein, 5-HT, DA, IL-4 and IL-10 were significantly decreased (P < 0.05). Compared with the model group, triptolide significantly alleviated the depressive behavior of rats, upregulated the expression of miR-137, decreased the levels of Iba-1 and iNOS protein and inhibited the levels of IL-1β and IL-6, and increased the expression of Arg1 protein and the levels of 5-HT, DA, IL-4 and IL-10 in hippocampus (P < 0.05). mir-137 inhibitor treatment significantly reversed the inhibitory effect of triptolide on the activation of microglia. Conclusion Triptolide ameliorates CUS-induced depression-like behavior in rats by up-regulating miR-137, which may be related to the regulation of microglial polarization.

R965

新疆维吾尔自治区自然科学基金资助项目（2021D01C513）