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

1 alpha,25-dihydroxyvitamin D-3 (VD3) 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 (PPAR alpha), 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). VD3 reversed cyanide-induced mitochondrial dysfunction in cells pretreated with Wy14,643, as reflected by restoration of cellular ATP and mitochondrial membrane potential (Delta Psi(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 VD3. The interaction of VD3 with UCP-2 was attributed to increased expression of I kappa B, an inhibitor of NF-kappa B (transcription factor that regulates UCP-2 expression). The increased I kappa B levels lead to reduced nuclear translocation and DNA binding of nuclear factor-kappa B. 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 VD3 pretreatment. It was concluded that VD3 blocks Wy14,643 enhancement of cyanide neurotoxicity by suppressing the redox-mediated transcriptional up-regulation of UCP-2, resulting in reduced mitochondrial proton leak and stabilization of mitochondrial function. (C) 2008 Wiley-Liss, Inc.