目的 探討雷公藤甲素通過上調(diào)miR-137調(diào)控小膠質(zhì)細(xì)胞極化改善抑郁癥的作用及潛在分子機(jī)制。方法 50只SD大鼠隨機(jī)分為對(duì)照組、模型組、雷公藤甲素組、雷公藤甲素＋NC抑制劑組和雷公藤甲素＋miR-137抑制劑組，每組10只。通過構(gòu)建慢性不可預(yù)知性應(yīng)激（CUS）抑郁大鼠模型，采用糖水偏好實(shí)驗(yàn)、強(qiáng)迫游泳實(shí)驗(yàn)和懸尾實(shí)驗(yàn)檢測(cè)大鼠的行為學(xué)變化，實(shí)時(shí)定量聚合酶鏈反應(yīng)（RT-qPCR）檢測(cè)大鼠海馬中miR-137的表達(dá)水平，Western blotting分別檢測(cè)大鼠海馬組織中離子鈣接頭蛋白分子-1（Iba-1）、誘導(dǎo)型一氧化氮合酶（iNOS）和精氨酸酶1（Arg1）蛋白表達(dá)，ELISA法檢測(cè)大鼠海馬中神經(jīng)遞質(zhì)5-羥色胺（5-HT）和多巴胺（DA）水平以及炎性因子白細(xì)胞介素-1β（IL-1β）、白細(xì)胞介素-6（IL-6）、白細(xì)胞介素-4（IL-4）、白細(xì)胞介素-10（IL-10）的水平。結(jié)果 與對(duì)照組比較，模型組大鼠糖水偏好百分比顯著降低，不動(dòng)時(shí)間顯著增加，體質(zhì)量明顯下降，海馬中miR-137表達(dá)顯著降低，Iba-1和iNOS蛋白以及IL-1β和IL-6水平顯著增加，Arg1蛋白、5-HT、DA、IL-4和IL-10水平顯著降低（P<0.05）。與模型組比較，雷公藤甲素顯著減輕大鼠的抑郁樣行為，上調(diào)miR-137表達(dá)，降低海馬組織中Iba-1和iNOS蛋白水平以及抑制IL-1β和IL-6水平，升高Arg1蛋白表達(dá)以及5-HT、DA、IL-4和IL-10水平（P<0.05）。miR-137抑制劑處理后顯著逆轉(zhuǎn)了雷公藤甲素對(duì)小膠質(zhì)細(xì)胞活化的抑制作用。結(jié)論 雷公藤甲素通過上調(diào)miR-137改善CUS誘導(dǎo)的大鼠抑郁樣行為，其機(jī)制可能與調(diào)節(jié)小膠質(zhì)細(xì)胞極化有關(guān)。

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

新疆維吾爾自治區(qū)自然科學(xué)基金資助項(xiàng)目（2021D01C513）