{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:34:02Z","timestamp":1793741642307,"version":"4.6.1"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,14]],"date-time":"2020-01-14T00:00:00Z","timestamp":1578960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100014012","name":"FightMND","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014012","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008714","name":"Motor Neurone Disease Research Institute of Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008714","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1103703"],"award-info":[{"award-number":["1103703"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Diacetyl\u2010bis(4\u2010methyl\u20103\u2010thiosemicarbazonato)copper<jats:sup>II<\/jats:sup>(Cu<jats:sup>II<\/jats:sup>(atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of Cu<jats:sup>II<\/jats:sup>(atsm) to inhibit ferroptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase\u20104 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of Cu<jats:sup>II<\/jats:sup>(atsm) was compared to the known antiferroptotic compound liproxstatin\u20101.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Cu<jats:sup>II<\/jats:sup>(atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC<jats:sub>50<\/jats:sub>: \u2248130 nM, within an order of magnitude of liproxstatin\u20101). Ni<jats:sup>II<\/jats:sup>(atsm) also prevented ferroptosis with similar potency, whereas ionic Cu<jats:sup>II<\/jats:sup>did not. In cell\u2010free systems, Cu<jats:sup>II<\/jats:sup>(atsm) and Ni<jats:sup>II<\/jats:sup>(atsm) inhibited Fe<jats:sup>II<\/jats:sup>\u2010induced lipid peroxidation, consistent with these compounds quenching lipid radicals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The antiferroptotic activity of Cu<jats:sup>II<\/jats:sup>(atsm) could therefore be the disease\u2010modifying mechanism being tested in ALS and PD trials. With potency<jats:italic>in vitro<\/jats:italic>approaching that of liproxstatin\u20101, Cu<jats:sup>II<\/jats:sup>(atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis\u2010related diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14881","type":"journal-article","created":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T20:13:41Z","timestamp":1572120821000},"page":"656-667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":139,"title":["Cu<sup>II<\/sup>(atsm) inhibits ferroptosis: Implications for treatment of neurodegenerative disease"],"prefix":"10.1111","volume":"177","author":[{"given":"Adam","family":"Southon","sequence":"first","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-5283","authenticated-orcid":false,"given":"Kathryn","family":"Szostak","sequence":"additional","affiliation":[{"name":"School of Chemistry and Bio21 Molecular Science and Biotechnology Institute The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla M.","family":"Acevedo","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista A.","family":"Dent","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Volitakis","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel A.","family":"Belaidi","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Barnham","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Crouch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-2427","authenticated-orcid":false,"given":"Scott","family":"Ayton","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Donnelly","sequence":"additional","affiliation":[{"name":"School of Chemistry and Bio21 Molecular Science and Biotechnology Institute The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-9069","authenticated-orcid":false,"given":"Ashley I.","family":"Bush","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health The University of Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.06.018"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx137"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3439-14.2015"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006958018049"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.06.025"},{"issue":"14","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"P6.105","DOI":"10.1212\/WNL.84.14_supplement.P6.105","article-title":"Reduction in cerebral antioxidant, glutathione (GSH), in patients with ALS: A preliminary study","volume":"84","author":"Choi I. 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