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Japan","award":["22K15742"],"award-info":[{"award-number":["22K15742"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-\u03b1-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-\u03b1 and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-\u03b1 and NO synthesis, whereas high concentrations (\u226530 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-\u03b1-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-\u03b1 remains unclear and merits further mechanistic investigations.<\/jats:p>","DOI":"10.3390\/ijms24043798","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T04:38:29Z","timestamp":1676349509000},"page":"3798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-\u03b1 Signaling"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9961-6275","authenticated-orcid":false,"given":"Mai","family":"Sakai","sequence":"first","affiliation":[{"name":"Department of Psychiatric Nursing, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4827-5922","authenticated-orcid":false,"given":"Zhiqian","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanne","family":"Picotin","sequence":"additional","affiliation":[{"name":"Medical Faculty, Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanami","family":"Oyama","sequence":"additional","affiliation":[{"name":"Department of Psychiatric Nursing, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Stellwagen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Center, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshie","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1068-9705","authenticated-orcid":false,"given":"Ko","family":"Matsui","sequence":"additional","affiliation":[{"name":"Super-network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6200-9279","authenticated-orcid":false,"given":"Miharu","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Psychiatric Nursing, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatsumi","family":"Yoshii","sequence":"additional","affiliation":[{"name":"Department of Psychiatric Nursing, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Furuyashiki","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Regenerative and Biomedical Engineering Medical Science, Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2628-880X","authenticated-orcid":false,"given":"Hiroaki","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"},{"name":"Department of Disaster Psychiatry, International Research Institute for Disaster Science, Tohoku University, Sendai 980-8573, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6458","DOI":"10.1002\/jcp.26479","article-title":"The multifaceted link between inflammation and human diseases","volume":"233","author":"Rajendran","year":"2018","journal-title":"J. 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