目的 基于小膠質(zhì)細胞的極化探討木犀草素發(fā)揮抗抑郁活性的相關(guān)機制。方法 將72只雄性大鼠隨機分為對照組，模型組，ABT-494組（10 mg/kg，JAK1抑制劑），木犀草素低、高劑量（30、60 mg/kg）組和木犀草素（60 mg/kg）+ABT-494（10 mg/kg）組，每組12只。除對照組外，其余組大鼠采用慢性不可預(yù)知性溫和應(yīng)激（CUMS）聯(lián)合孤養(yǎng)復(fù)制抑郁大鼠模型。建模成功后ig相應(yīng)劑量的藥物進行干預(yù)，1次/d，連續(xù)28 d。分別于造模前1 d、造模結(jié)束后和給藥結(jié)束后，采用糖水偏好實驗和強迫游泳實驗對大鼠抑郁樣行為進行評估；免疫熒光雙染法檢測大鼠海馬齒狀回（DG）小膠質(zhì)細胞中離子鈣結(jié)合銜接分子-1 （Iba-1）和誘導(dǎo)型一氧化氮合酶（iNOS）的表達；ELISA檢測海馬組織炎性因子白細胞介素（IL）-6、腫瘤壞死因子-α（TNF-α）、IL-4、IL-10的水平；Western blotting檢測海馬組織Janus激酶1（JAK1）/信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3（STAT3）通路相關(guān)蛋白表達。結(jié)果 與對照組比較，模型組大鼠體質(zhì)量、糖水偏好度、海馬組織IL-4、IL-10水平顯著降低，強迫游泳時不動時間、海馬DG區(qū)Iba-1/iNOS共表達的陽性細胞數(shù)、海馬組織TNF-α、IL-6水平和p-JAK1/JAK1、p-STAT3/STAT3值顯著增加（P<0.05）；與模型組比較，ABT-494組、木犀草素+ABT-494組和木犀草素低、高劑量組大鼠體質(zhì)量、糖水偏好度、海馬組織IL-4、IL-10水平顯著增加，強迫游泳時不動時間、海馬DG區(qū)Iba-1/iNOS共表達的陽性細胞數(shù)、海馬組織TNF-α、IL-6水平和p-JAK1/JAK1、p-STAT3/STAT3比值顯著降低（P<0.05）；且木犀草素和ABT-494聯(lián)合使用后作用優(yōu)于兩者單獨應(yīng)用。結(jié)論 木犀草素的抗抑郁作用可能與抑制JAK1/STAT3信號通路的激活，進而抑制小膠質(zhì)細胞向M1型活化有關(guān)。

Objective Based on the polarization of microglia, to explore the relevant mechanism of luteolin exerting antidepressant activity. Methods Seventy-two male rats were randomly divided into control group, model group, ABT-494 group (10 mg/kg), luteolin low (30 mg/kg), high (60 mg/kg) dose groups, luteolin (60 mg/kg) + ABT-494 (10 mg/kg) group, 12 rats in each group. Except for control group, rats in the other groups were treated with chronic unpredictable mild stress (CUMS) combined with orphan rearing to replicate depression rat models. After the modeling was successful, the corresponding dose of drugs was given to the stomach for intervention, once a day, for 28 consecutive days. On one day before modeling, after modeling, and after drug administration respectively, sugar water preference experiment and forced swimming experiment were used to evaluate the depressive behavior of rats; immunofluorescence double staining method was used to detect the expression of Iba-1 and iNOS in rat hippocampal dentate gyrus (DG) microglia; ELISA was used to detect the levels of inflammatory factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-4 and IL-10 in hippocampus; Western blotting was used to detect the expression of Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathway related proteins in hippocampus. Results Compared with control group, the body weight, sugar water preference, and the levels of hippocampal IL-4 and IL-10 reduced significantly in the model group, the immobility time during forced swimming, the number of positive cells co-expressed with ionized calcium-binding adapter molecule-1 (Iba-1)/inducible nitric oxide synthase (iNOS) in the hippocampal DG area, and the levels of TNF-α and IL-6 in hippocampus and the ratios of p-JAK1/JAK1 and p-STAT3/STAT3 increased significantly (P<0.05). Compared with the model group, the body weight, sugar water preference, and the levels of hippocampal IL-4 and IL-10 increased significantly in the luteolin low and high dose groups, the immobility time during forced swimming, the number of positive cells co-expressed with Iba-1/iNOS in the hippocampal DG area, the levels of TNF-α and IL-6 in hippocampus and the ratios of p-JAK1/JAK1 and p-STAT3/STAT3 reduced significantly (P<0.05). In addition, the combined use of luteolin and JAK1 inhibitor ABT-494 could inhibit the JAK1/ STAT3 signaling pathway and improve depression-like behavior in model rats better than the two alone. Conclusion The antidepressant effect of luteolin may be related to the inhibition of the activation of JAK1/STAT3 signaling pathway and the inhibition of the activation of microglia to M1 type.

R285.5

湖南省中醫(yī)藥科研計劃項目（2021072）；湖南省教育廳科學(xué)研究項目（19C1415）；湖南省衛(wèi)生健康委科研項目（20200312）