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We report that <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> induces neuronal cell death through an atypical calpain\u2010dependent necroptosis pathway that initiates with downstream activation of c\u2010Jun N\u2010terminal kinase 1 (<jats:styled-content style=\"fixed-case\">JNK<\/jats:styled-content>1) and increased expression of receptor\u2010interacting protein 1 (<jats:styled-content style=\"fixed-case\">RIP<\/jats:styled-content>\u20101) and is accompanied by cleavage and mitochondrial release\/nuclear translocation of apoptosis\u2010inducing factor, mitochondrial release of Smac\/<jats:styled-content style=\"fixed-case\">DIABLO<\/jats:styled-content>, and inhibition of the anti\u2010apoptotic protein X\u2010linked inhibitor of apoptosis (<jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content>). Coinciding with apoptosis\u2010inducing factor nuclear translocation, <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> induces phosphorylation of the necroptosis\u2010associated histone H2A family member H2<jats:styled-content style=\"fixed-case\">AX<\/jats:styled-content>, which is known to contribute to lethal <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> degradation. These signals are inhibited in neuronal cells that express constitutively activated <jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> and\/or <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3\u2010K\/Akt survival pathways, allowing them to resist <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>\u2010induced cell death. The data indicate that <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> has neurotoxic activity and identify a novel calpain\u2010dependent necroptosis pathway that includes <jats:styled-content style=\"fixed-case\">JNK<\/jats:styled-content>1 activation and <jats:styled-content style=\"fixed-case\">RIP<\/jats:styled-content>\u20101 expression.\n<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\/jnc13029-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>A growing body of evidence indicates that valproic acid (VPA) has neurotoxic activity, the mechanism of which is still poorly understood. We report, for the first time, that VPA activates a previously unrecognized calpain\u2010dependent necroptosis cascade that initiates with JNK1 activation and involves AIF cleavage\/nuclear translocation and H2AX phosphorylation as well as an altered Smac\/DIABLO to XIAP balance.<\/jats:p>","DOI":"10.1111\/jnc.13029","type":"journal-article","created":{"date-parts":[[2015,1,10]],"date-time":"2015-01-10T13:35:36Z","timestamp":1420896936000},"page":"174-186","source":"Crossref","is-referenced-by-count":45,"title":["Valproic acid induces neuronal cell death through a novel calpain\u2010dependent necroptosis pathway"],"prefix":"10.1111","volume":"133","author":[{"given":"Dominique","family":"Bollino","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Maryland Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Balan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of 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