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1α,25‐dihydroxyvitamin D 3 attenuates cyanide‐induced neurotoxicity by inhibiting uncoupling protein‐2 up‐regulation
Author(s) -
Li L.,
Prabhakaran K.,
Zhang X.,
Zhang L.,
Liu H.,
Borowitz J.L.,
Isom G.E.
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21596
Subject(s) - oxidative stress , neurotoxicity , reactive oxygen species , chemistry , cyanide , glutathione , uncoupling protein , neuroprotection , mitochondrion , programmed cell death , oxidative phosphorylation , biochemistry , pharmacology , biology , microbiology and biotechnology , apoptosis , toxicity , inorganic chemistry , organic chemistry , adipose tissue , brown adipose tissue , enzyme
1α,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‐α (PPARα), 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 (ΔΨ 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 IκB, an inhibitor of NF‐κB (transcription factor that regulates UCP‐2 expression). The increased IκB levels lead to reduced nuclear translocation and DNA binding of nuclear factor‐κB. 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 3 pretreatment. It was concluded that VD 3 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. © 2008 Wiley‐Liss, Inc.