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ToxSci Advance Access originally published online on June 16, 2006
Toxicological Sciences 2006 93(1):136-145; doi:10.1093/toxsci/kfl039
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PPAR{alpha}-Mediated Upregulation of Uncoupling Protein-2 Switches Cyanide-Induced Apoptosis to Necrosis in Primary Cortical Cells

Li Li, Krishnan Prabhakaran, Xun Zhang, Joseph L. Borowitz and Gary E. Isom1

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-1333

Received March 30, 2006; accepted June 5, 2006

Peroxisome proliferator–activated receptor alpha (PPAR{alpha}) is a member of the nuclear factor PPAR family that regulates a variety of cellular functions, including lipid metabolism, cellular oxidative stress defense, and inflammatory responses. Based on the report that Wy14,643, a PPAR{alpha} agonist, can upregulate uncoupling protein-2 (UCP-2), this study was conducted in primary cortical cells to determine if PPAR{alpha} activation enhances cyanide-induced neurotoxicity through changes in the level of UCP-2. PCR and Western blot analysis showed that Wy14,643 upregulated UCP-2 transcriptionally over a 12-h period. This response was mediated by PPAR{alpha} since it was blocked by MK886, a selective PPAR{alpha} antagonist. The effect of UCP-2 upregulation on the cytotoxic response to cyanide was quantitated by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (apoptosis) and propidium iodide staining (necrosis). Wy14,643 switched the mode of cyanide-induced cell death from apoptosis to necrosis. Cell death was preceded by marked mitochondrial dysfunction, as reflected by depletion of ATP and reduction of the mitochondrial membrane potential ({Delta}{Psi}m). Knock down of UCP-2 expression by RNA interference blocked the Wy14,643-mediated enhancement of cyanide-induced mitochondrial dysfunction and the switch of the cell death mode, thus confirming that the response was mediated by upregulation of UCP-2. This study shows that PPAR{alpha} activation can upregulate UCP-2 expression, which in turn enhances cyanide-induced necrotic cell death through an increase of mitochondrial dysfunction.

Key Words: PPAR{alpha}; cyanide; cell death; apoptosis; necrosis; UCP-2; mitochondrial function.


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