{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T17:48:24Z","timestamp":1760982504355,"version":"3.40.4"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2008,1,8]],"date-time":"2008-01-08T00:00:00Z","timestamp":1199750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>1\u03b1,25\u2010dihydroxyvitamin D<jats:sub>3<\/jats:sub> (VD<jats:sub>3<\/jats:sub>) is a neuroprotectant that can reduce cytotoxicity produced by a variety of toxicants. The mechanism of the neuroprotection was studied in rat primary cortical cells in which Wy14,643, an agonist of peroxisome proliferator activated receptor\u2010\u03b1 (PPAR\u03b1), enhances cyanide (KCN) neurotoxicity. In this cell model, Wy14,643 pretreatment enhanced cyanide\u2010induced cell death, and the increased cell death was linked to up\u2010regulation of uncoupling protein\u20102 (UCP\u20102). VD<jats:sub>3<\/jats:sub> reversed cyanide\u2010induced mitochondrial dysfunction in cells pretreated with Wy14,643, as reflected by restoration of cellular ATP and mitochondrial membrane potential (\u0394\u03a8<jats:sub>m<\/jats:sub>). Analysis of cellular state 4 oxygen consumption showed increased mitochondrial uncoupling accompanied by up\u2010regulation of UPC\u20102. The uncoupling was attenuated by prior treatment with VD<jats:sub>3<\/jats:sub>. The interaction of VD<jats:sub>3<\/jats:sub> with UCP\u20102 was attributed to increased expression of I\u03baB, an inhibitor of NF\u2010\u03baB (transcription factor that regulates UCP\u20102 expression). The increased I\u03baB levels lead to reduced nuclear translocation and DNA binding of nuclear factor\u2010\u03baB. The role of oxidative stress in the response was then evaluated. Cotreatment with Wy14,643 and cyanide markedly increased reactive oxygen species generation and decreased reduced glutathione levels. The oxidative stress was blocked by VD<jats:sub>3<\/jats:sub> pretreatment. It was concluded that VD<jats:sub>3<\/jats:sub> blocks Wy14,643 enhancement of cyanide neurotoxicity by suppressing the redox\u2010mediated transcriptional up\u2010regulation of UCP\u20102, resulting in reduced mitochondrial proton leak and stabilization of mitochondrial function. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.21596","type":"journal-article","created":{"date-parts":[[2008,1,8]],"date-time":"2008-01-08T23:16:49Z","timestamp":1199834209000},"page":"1397-1408","source":"Crossref","is-referenced-by-count":19,"title":["1\u03b1,25\u2010dihydroxyvitamin D<sub>3<\/sub> attenuates cyanide\u2010induced neurotoxicity by inhibiting uncoupling protein\u20102 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