暨南大学陈家旭等研究人员合作发现，木犀草素通过PPARγ依赖机制促进Arginase-1+小胶质细胞表型，来改善小鼠慢性应激诱导的抑郁样行为。相关论文于2024年11月4日在线发表在《中国药理学报》杂志上。

研究人员探讨了木犀草素（LUT）通过何种分子机制调节小胶质细胞在小鼠抑郁样行为中的功能表型。小鼠暴露于慢性约束应激（CRS）7周，并在最后4周给予LUT（10、30、40 mg/kg每天，口服）。研究人员发现，LUT治疗显著改善了抑郁样行为并减少了海马的炎症。LUT治疗诱导促炎小胶质细胞发生抗炎Arg-1⁺表型极化，这与其抗抑郁作用相关。此外，研究人员还发现，LUT浓度依赖性地增加了LPS+ATP处理的小胶质细胞和CRS暴露小鼠海马中的PPARγ表达，促进了随后NLRP3炎症小体的抑制。

分子动力学（MD）模拟和微尺度热泳（MST）分析证实了LUT与过氧化物酶体增殖物激活受体γ（PPARγ）之间的直接相互作用。通过使用PPARγ拮抗剂GW9662，研究人员证明了LUT驱动的保护作用，既在体内也在体外，均来源于靶向PPARγ。首先，当PPARγ被阻断时，不再检测到LUT诱导的Arg-1⁺小胶质细胞。接下来，LUT介导的NLRP3炎症小体抑制和促炎细胞因子产生下调被PPARγ抑制逆转。最后，LUT的保护作用，减轻了小胶质细胞对突触的吞噬并防止了CRS暴露小鼠海马中明显的突触丧失，均被阻断PPARγ所消除。

总之，该研究表明，LUT通过PPARγ依赖机制促进Arg-1⁺小胶质细胞表型，从而改善CRS诱导的抑郁样行为，减轻小胶质细胞的促炎反应，并逆转小胶质细胞吞噬介导的突触丧失。

研究人员表示，越来越多的证据表明，神经炎症在抑郁症的病理中发挥着重要作用，抑郁症是一种严重的精神疾病，其全球患病率不断上升。尽管调节小胶质细胞表型被认为是一种有前景的治疗策略，但有效的治疗方法仍然缺乏。先前的研究表明，LUT具有抗炎作用，并对慢性应激诱导的抑郁症具有益处。

附：英文原文

Title: Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1+ microglial phenotype via a PPARγ-dependent mechanism

Author: Yuan, Nai-jun, Zhu, Wen-jun, Ma, Qing-yu, Huang, Min-yi, Huo, Rou-rou, She, Kai-jie, Pan, Jun-ping, Wang, Ji-gang, Chen, Jia-xu

Issue&Volume: 2024-11-04

Abstract: Accumulating evidence shows that neuroinflammation substantially contributes to the pathology of depression, a severe psychiatric disease with an increasing prevalence worldwide. Although modulating microglial phenotypes is recognized as a promising therapeutic strategy, effective treatments are still lacking. Previous studies have shown that luteolin (LUT) has anti-inflammatory effects and confers benefits on chronic stress-induced depression. In this study, we investigated the molecular mechanisms by which LUT regulates the functional phenotypes of microglia in mice with depressive-like behaviors. Mice were exposed to chronic restraint stress (CRS) for 7 weeks, and were administered LUT (10, 30, 40mg·kg1 ·day1, i.g.) in the last 4 weeks. We showed that LUT administration significantly ameliorated depressive-like behaviors and decreased hippocampal inflammation. LUT administration induced pro-inflammatory microglia to undergo anti-inflammatory arginase (Arg)-1+ phenotypic polarization, which was associated with its antidepressant effects. Furthermore, we showed that LUT concentration-dependently increased the expression of PPARγ in LPS+ATP-treated microglia and the hippocampus of CRS-exposed mice, promoting the subsequent inhibition of the NLRP3 inflammasome. Molecular dynamics (MD) simulation and microscale thermophoresis (MST) analysis confirmed a direct interaction between LUT and peroxisome proliferator-activated receptor gamma (PPARγ). By using the PPARγ antagonist GW9662, we demonstrated that LUT-driven protection, both in vivo and in vitro, resulted from targeting PPARγ. First, LUT-induced Arg-1+ microglia were no longer detected when PPARγ was blocked. Next, LUT-mediated inhibition of the NLRP3 inflammasome and downregulation of pro-inflammatory cytokine production were reversed by the inhibition of PPARγ. Finally, the protective effects of LUT, which attenuated the microglial engulfment of synapses and prevented apparent synapse loss in the hippocampus of CRS-exposed mice, were eliminated by blocking PPARγ. In conclusion, this study showed that LUT ameliorates CRS-induced depressive-like behaviors by promoting the Arg-1+ microglial phenotype through a PPARγ-dependent mechanism, thereby alleviating microglial pro-inflammatory responses and reversing microglial phagocytosis-mediated synapse loss.

DOI: 10.1038/s41401-024-01402-9

Source: https://www.nature.com/articles/s41401-024-01402-9