1Alpha,25-dihydroxyvitamin D3 attenuates cyanide-induced neurotoxicity by inhibiting uncoupling protein-2 up-regulation

Journal of Neuroscience Research
Li LiGary E Isom

Abstract

1Alpha,25-dihydroxyvitamin D(3) (VD(3)) 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-alpha (PPARalpha), enhances cyanide (KCN) neurotoxicity. In this cell model, Wy14,643 pretreatment enhanced cyanide-induced cell death, and the increased cell death was linked to up-regulation of uncoupling protein-2 (UCP-2). VD(3) reversed cyanide-induced mitochondrial dysfunction in cells pretreated with Wy14,643, as reflected by restoration of cellular ATP and mitochondrial membrane potential (DeltaPsi(m)). Analysis of cellular state 4 oxygen consumption showed increased mitochondrial uncoupling accompanied by up-regulation of UPC-2. The uncoupling was attenuated by prior treatment with VD(3). The interaction of VD(3) with UCP-2 was attributed to increased expression of IkappaB, an inhibitor of NF-kappaB (transcription factor that regulates UCP-2 expression). The increased IkappaB levels lead to reduced nuclear translocation and DNA binding of nuclear factor-kappaB. The role of oxidative stress in the response was then evaluated. Cotreatment with Wy...Continue Reading

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