Hydralazine rescues PC12 cells from acrolein-mediated death.
Acrolein, a major lipid peroxidation product, has been associated with both CNS trauma and neurodegenerative diseases. Because of its long half-life, acrolein is a potent endogenous toxin capable of killing healthy cells during the secondary injury process. Traditionally, attempts to intervene in the process of progressive cell death after the primary injury have included scavenging reactive oxygen species (so-called free radicals). The animal data supporting such an approach have generally been positive, but all human clinical trials attempting a similar outcome in human CNS injury have failed. New drugs that might reduce toxicity by scavenging the products of lipid peroxidation present a promising, and little investigated, therapeutic approach. Hydralazine, a well-known treatment for hypertension, has been reported to react with acrolein, forming hydrazone in cell-free systems. In the companion paper, we have established an acrolein-mediated cell injury model using PC12 cells in vitro. Here we test the hypothesis that the formation of hydrazone adducts with acrolein is able to reduce acrolein toxicity and spare a significant percentage of the population of PC12 cells from death. Concentrations of approximately 1 mM of this aldehyde scavenger can rescue over 80% of the population of PC12 cells. This study provides a basis for a new pharmacological treatment to reduce the effects of secondary injury in the damaged and/or diseased nervous system. In particular, we describe the need for new drugs that possess aldehyde scavenging properties but do not interfere with the regulation of blood pressure.
Liu-Snyder
Peishan
P
Center for Paralysis Research, Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907-2096, USA.
Borgens
Richard Ben
RB
Shi
Riyi
R
D000171:Acrolein / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005434:Flow Cytometry / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles
D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D006830:Hydralazine; D000171:Acrolein; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D005978:Glutathione