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

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

机构地区：[1]Department of Critical Care Medicine,Shenzhen Clinical Research Center for Geriatric,and Guangdong Provincial Clinical Research Center for Geriatrics,Integrated Chinese and Western Medicine Postdoctoral Research Station,Shenzhen Peopleʼs Hospital(The Second Clinical Medical College,Jinan University),Shenzhen,518020,China [2]Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine,School of Traditional Chinese Medicine,Jinan University,Guangzhou,510632,China [3]Department of Clinical Molecular Biology,University of Oslo and Akershus University Hospital,1478,Lørenskog,Norway [4]Guangdong Second Provincial General Hospital,Postdoctoral Research Station of Basic Medicine,Jinan University,Guangzhou,510632,China [5]School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing,100029,China [6]State Key Laboratory for Quality Assurance and Sustainable Use of Dao-di Herbs,Artemisinin Research Center,and Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing,100700,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期575-591,共17页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(Nos.82304990,82474365 and 81973748);the Key Program of National Natural Science Foundation of China(No.82430126);the National Key R&D Program of China(No.2023YFE0209500);the China Postdoctoral Science Foundation(No.2023M732380);the Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine(No.202102010014);the National Training Program of Innovation and Entrepreneurship for Undergraduates,China(No.202310559128);Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University.

摘　　要：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(10,30,40 mg·kg^(−1)·day^(−1),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 PPARγin 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 PPARγantagonist 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 PPARγwas 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

关 键 词：depression LUTEOLIN NEUROINFLAMMATION MICROGLIA PPARY PHAGOCYTOSIS 

分 类 号：R285[医药卫生—中药学] R285.5[医药卫生—中医学]