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This therapeutic gap stems from two key challenges: the inability to deliver neuroprotective drugs before reperfusion and limited understanding of post-reperfusion events leading to delayed neurodegeneration. Zn2+ is an important contributor to ischemic brain injury, with mitochondrial Zn2+ uptake playing a central role in its neurotoxic effects. Ongoing Zn2+ accumulation occurs through the mitochondrial Ca2+ uniporter (MCU) in selectively vulnerable CA1 neurons after transient ischemia, contributing to delayed mitochondrial dysfunction. We previously demonstrated that post-ischemic administration of the non-selective MCU antagonist, ruthenium red attenuated neuronal damage in both an ex vivo oxygen\u2013glucose deprivation (OGD) mouse brain slice model and in an in vivo rat cardiac arrest (CA) model. In the present study, we test post-ischemic treatment with Ru265, a novel selective MCU blocker, in both ischemic models. In the slice model, OGD induced delayed Zn2+ accumulation in CA1 neuronal mitochondria (as previously reported), followed by late-onset persistent mitochondrial depolarization and sustained elevation of cytoplasmic Ca2+ levels, indicating loss of Ca2+ homeostasis. Application of Ru265 after OGD termination inhibited the mitochondrial Zn2+ accumulation and largely prevented subsequent mitochondrial depolarization and loss of cytosolic Ca2+ homeostasis. In the CA model, intravenous Ru265 administration during cardiopulmonary resuscitation largely mitigated mitochondrial damage, markedly reduced neuronal injury and improved behavioral outcomes 20\u201324\u00a0h after ischemia. These findings suggest that post-ischemic MCU blockade may constitute a promising neuroprotective therapeutic strategy.<\/jats:p>","DOI":"10.1042\/cs20261842","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:46:58Z","timestamp":1790167618000},"page":"2325-2344","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Post-ischemic inhibition of the mitochondrial Ca2+ uniporter with Ru265 protects in\n                    <i>ex vivo<\/i>\n                    and\n                    <i>in vivo<\/i>\n                    models of cerebral ischemia"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0730-0936","authenticated-orcid":false,"given":"Yuliya\u00a0V.","family":"Medvedeva","sequence":"first","affiliation":[{"name":"1Department of Neurology, University of California Irvine, Irvine, CA 92697, United 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