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However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high\u2010mobility group box 1 (HMGB1)\/TLR4\/NF\u2010\u03baB and TNF\u2010\u03b1\/TNFR1\/NF\u2010\u03baB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The effects of chronic unpredictable mild stress (CUMS) on wild\u2010type (WT) and TLR4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice were examined. Antidepressant\u2010like effects of arctigenin were tested using the CUMS\u2010induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1\/TLR4\/NF\u2010\u03baB and TNF\u2010\u03b1\/TNFR1\/NF\u2010\u03baB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1\u2010 or TNF\u2010\u03b1\u2010stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF\u2010\u03b1 and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co\u2010immunoprecipitation assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, compared with WT mice. Arctigenin exhibited antidepressant\u2010like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF\u2010\u03b1 and TNFR1 interactions, and suppressed both HMGB1\/TLR4\/NF\u2010\u03baB and TNF\u2010\u03b1\/TNFR1\/NF\u2010\u03baB signalling pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Arctigenin has antidepressant\u2010like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1\/TLR4\/NF\u2010\u03baB and TNF\u2010\u03b1\/TNFR1\/NF\u2010\u03baB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15261","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T03:21:32Z","timestamp":1601263292000},"page":"5224-5245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":272,"title":["Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1\/TLR4\/NF\u2010\u03baB and TNF\u2010\u03b1\/TNFR1\/NF\u2010\u03baB pathways"],"prefix":"10.1111","volume":"177","author":[{"given":"Xiang","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu\u2010Nan","family":"Piao","sequence":"additional","affiliation":[{"name":"Department of Neurology Affliated Hospital of Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumie","family":"Aosai","sequence":"additional","affiliation":[{"name":"Department of Infection and Host Defense, Graduate School of Medicine Shinshu University  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Yu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Hui","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue\u2010Xian","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology Affliated Hospital of Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology Affliated Hospital of Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu\u2010Ri","family":"Piao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6998-2602","authenticated-orcid":false,"given":"Xuejun","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8315-5918","authenticated-orcid":false,"given":"Lian\u2010Xun","family":"Piao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy Yanbian University  Yanji Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"issue":"9","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1080\/00365540310015683","article-title":"Toll\u2010like receptors and their signaling mechanisms","volume":"35","author":"Akira S.","year":"2003","journal-title":"Scandinavian Journal of Infectious Diseases"},{"issue":"1","key":"e_1_2_12_3_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander S. 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