1Alpha,25-dihydroxyvitamin D3 attenuates cyanide-induced neurotoxicity by inhibiting uncoupling protein-2 up-regulation.
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 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.
Li
L
L
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
Prabhakaran
K
K
Zhang
X
X
Zhang
L
L
Liu
H
H
Borowitz
J L
JL
Isom
G E
GE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003486:Cyanides / Q000633:toxicity*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071246:Uncoupling Protein 2; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D003486:Cyanides; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009153:Mutagens; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C006253:pirinixic acid; D005978:Glutathione