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Here, we further studied its downstream mechanisms and the role of the autophagy inhibitors 3\u2010methyladenine (3\u2010MA) and bafilomycin A1 (BAF). A 20\u2010min global cerebral I\/R injury model was constructed using the 4\u2010vessel occlusion (4\u2010VO) method in male rats. 3\u2010MA and BAF were injected into the lateral ventricle 1\u2009h before ischemia. Spatial and activation changes of proteins were detected by immunofluorescence (IF), and protein interaction was determined by immunoprecipitation (IP). The phosphorylation of H2AX (\u03b3\u2010H2AX) and activation of mixed lineage kinase domain\u2010like protein (p\u2010MLKL) occurred as early as 6\u2009h after reperfusion. RIP3, AIF, and cyclophilin A (CypA) in the neurons after I\/R injury were spatially overlapped around and within the nucleus and combined with each other after reperfusion. The survival rate of CA1 neurons in the 3\u2010MA and BAF groups was significantly higher than that in the I\/R group. Autophagy was activated significantly after I\/R injury, which was partially inhibited by 3\u2010MA and BAF. Pretreatment with both 3\u2010MA and BAF almost completely inhibited nuclear translocation, spatial overlap, and combination of RIP3, AIF, and CypA proteins. These findings suggest that after global cerebral I\/R injury, RIP3, AIF, and CypA translocated into the nuclei and formed the DNA degradation complex RIP3\/AIF\/CypA in hippocampal CA1 neurons. Pretreatment with autophagy inhibitors could reduce neuronal necroptosis by preventing the formation of the RIP3\/AIF\/CypA complex and its nuclear translocation.<\/jats:p>","DOI":"10.1002\/jnr.25301","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T08:05:10Z","timestamp":1706774710000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Autophagy inhibitors 3\u2010MA and BAF may attenuate hippocampal neuronal necroptosis after global cerebral ischemia\u2013reperfusion injury in male rats by inhibiting the interaction of the\n                    <scp>RIP3<\/scp>\n                    \/\n                    <scp>AIF<\/scp>\n                    \/\n                    <scp>CypA<\/scp>\n                    complex"],"prefix":"10.1002","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7289-2613","authenticated-orcid":false,"given":"Chen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renhui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Non\u2010coding RNA Transformation Research of Anhui Higher Education Institutes First 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