Tofacitinib prevents depressive-like behaviors through decreased hippocampal microgliosis and increased BDNF levels in both LPS-induced and CSDS-induced mice  

作　　者：Ya-nan Gao Kai-jun Pan Yong-mei Zhang Ying-bei Qi Wen-gang Chen Ting Zhou Hai-chao Zong Hao-ran Guo Jin-wen Zhao Xing-chen Liu Zi-tong Cao Ze Chen Tao Yin Yi Zang Jia Li 

机构地区：[1]Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University,Nanjing,210009,China [2]National Center for Drug Screening,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310024,China [4]University of Chinese Academy of Sciences,Beijing,100049,China [5]Lingang Laboratory,Shanghai,200120,China

出　　处：《Acta Pharmacologica Sinica》2025年第2期353-365,共13页中国药理学报(英文版)

基　　金：founded by National Natural Science Foundation of China grant 82001572;National Natural Science Foundation of China grant 81971265;National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”grant 2018ZX09711002-007-002;Shanghai Commission of Science and Technology grant 2021000003;Shanghai Science and Technology Development Funds(Shanghai Commission of Science and Technology)grant 19JC1416300.

摘　　要：Depressive disorders are a global mental health challenge that is closely linked to inflammation,especially in the post-COVID-19 era.The JAK-STAT pathway,which is primarily associated with inflammatory responses,is not fully characterized in the context of depressive disorders.Recently,a phase 3 retrospective cohort analysis heightened that the marketed JAK inhibitor tofacitinib is beyond immune diseases and has potential for preventing mood disorders.Inspired by these clinical facts,we investigated the role of the JAK-STAT signaling pathway in depression and comprehensively assessed the antidepressant effect of tofacitinib.We found that aberrant activation of the JAK-STAT pathway is highly conserved in the hippocampus of classical depressive mouse models:LPS-induced and chronic social defeat stress(CSDS)-induced depressive mice.Mechanistically,the JAK-STAT pathway mediates proinflammatory cytokine production and microgliosis,leading to synaptic defects in the hippocampus of both depressive models.Remarkably,the JAK inhibitor tofacitinib effectively reverses these phenomena,contributing to its antidepressant effect.These findings indicate that the JAK/STAT pathway could be implicated in depressive disorders,and suggest that the JAK inhibitor tofacitinib has a potential translational implication for preventing mood disorders far beyond its current indications.

关 键 词：tofacitinib depression JAK-STAT pathway MICROGLIOSIS synaptic defects 

分 类 号：R97[医药卫生—药品]