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ToxSci Advance Access published online on June 16, 2006
Toxicological Sciences, 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
Received March 30, 2006
Accepted June 5, 2006

Neurotoxicology

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

L. Li 1, K. Prabhakaran 1, X. Zhang 1, J. L. Borowitz 1, and G. E. Isom 1 *

1 Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University West Lafayette, IN 47907-1333

* To whom correspondence should be addressed.
G. E. Isom, E-mail: geisom{at}purdue.edu


  Abstract

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 up-regulate 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 up-regulated 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 up-regulation on the cytotoxic response to cyanide was quantitated by TUNEL (apoptosis) and PI 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). Knockdown 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 the response was mediated by up-regulation of UCP-2. This study shows that PPAR{alpha} activation can up-regulate UCP-2 expression, which in turn enhances cyanide-induced necrotic cell death through an increase of mitochondrial dysfunction.

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