{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:53:00Z","timestamp":1790823180665,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 NIA AG014930"],"award-info":[{"award-number":["P01 NIA AG014930"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>N\u2010acetylcysteine (NAC) is a clinically approved thiol\u2010containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an \u201cantioxidant,\u201d poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5\u2010lipoxygenase (ALOX5) knockout mice, and viral\u2010gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NAC prevented hemin\u2010induced ferroptosis by neutralizing toxic lipids generated by arachidonate\u2010dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione\u2010dependent enzymes such as glutathione\n                      <jats:italic>S<\/jats:italic>\n                      \u2010transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E\n                      <jats:sub>2<\/jats:sub>\n                      (PGE\n                      <jats:sub>2<\/jats:sub>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE\n                      <jats:sub>2<\/jats:sub>\n                      in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854\u2013872\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.25356","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T00:41:40Z","timestamp":1538959300000},"page":"854-872","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":285,"title":["N\u2010acetylcysteine targets 5 lipoxygenase\u2010derived, toxic lipids and can synergize with prostaglandin E\n                    <sub>2<\/sub>\n                    to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice"],"prefix":"10.1002","volume":"84","author":[{"given":"Saravanan S.","family":"Karuppagounder","sequence":"first","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Alin","sequence":"additional","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brand","sequence":"additional","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan W.","family":"Bourassa","sequence":"additional","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Institute Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra M.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Department of Psychology University of Alberta Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colby A.","family":"Nadeau","sequence":"additional","affiliation":[{"name":"Department of Psychology University of Alberta Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Sperling Center for Hemorrhagic Stroke Recovery, Burke Neurological Institute White Plains NY"},{"name":"Brain and Mind Research Institute and Department of Neurology Weill Cornell Medicine New York NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California at Santa Cruz Santa Cruz CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology New York Medical College Valhalla NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Darley\u2010Usmar","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham Birmingham AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Vanderbilt University Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginger L.","family":"Milne","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Vanderbilt University Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Pratico","sequence":"additional","affiliation":[{"name":"Alzheimer's Center at Temple University, Lewis Katz School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore R.","family":"Holman","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California at Santa Cruz Santa Cruz CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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