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However, intracellular copper, when improperly buffered, can also lead to cell death. Given the growing interest in the use of copper in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of this compound on the surround parenchyma\u2014namely neurons and astrocytes in vitro. Here, we show that astrocytes were highly sensitive to CuES toxicity while neurons were surprisingly resistant, a vulnerability profile that is opposite of what has been described for zinc and other toxins. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cuproptosis, a form of copper\u2010regulated cell death, such as inhibition of mitochondrial respiration or knock\u2010down of ferredoxin 1 (FDX1), did not block CuES toxicity to astrocytes. CuES toxicity was also unaffected by inhibitors of apoptosis, necrosis or ferroptosis. However, we did detect the presence of lipid peroxidation products in CuES\u2010treated astrocytes, indicating that oxidative stress is a mediator of CuES\u2010induced glial toxicity. Indeed, treatment with anti\u2010oxidants mitigated CuES\u2010induced cell death in astrocytes indicating that oxidative stress is a mediator of CuES\u2010induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes with zinc plus pyrithione was strikingly protective against CuES toxicity. As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15961-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15961","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T09:05:47Z","timestamp":1694595947000},"page":"277-295","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Copper induces neuron\u2010sparing, ferredoxin 1\u2010independent astrocyte toxicity mediated by oxidative stress"],"prefix":"10.1111","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-9497","authenticated-orcid":false,"given":"Jenna R.","family":"Gale","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Pittsburgh Institute for Neurodegenerative Diseases University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Hartnett\u2010Scott","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Pittsburgh Institute for Neurodegenerative Diseases University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline M.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Pittsburgh Institute for Neurodegenerative Diseases University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5185-1118","authenticated-orcid":false,"given":"Paul A.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Neurology and the F.M. 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