ToxSci Advance Access originally published online on July 1, 2008
Toxicological Sciences 2008 105(2):395-407; doi:10.1093/toxsci/kfn132
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Domoic Acid Impairment of Cardiac Energetics
Department of Pharmacology and Toxicology, University of Otago Faculty of Medicine, Dunedin, New Zealand
1 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, University of Otago, PO Box 913, Dunedin, Otago 9054, New Zealand. Fax: +64-(0)3-479-9140. E-mail: joanne.harrison{at}stonebow.otago.ac.nz.
Received April 30, 2008; accepted June 24, 2008
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Abstract |
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Excitatory mediated neuronal injury has been shown to involve a complex cascade of events. However, the associated cardiac damage reported in humans and marine animals following exposure to excitotoxins has not been well characterized. We hypothesized that the excitotoxin domoic acid can traverse cardiac cell membranes and elicit a deleterious effect on cardiac mitochondrial energetics. Domoic acid (0.05–0.25µM; 10 min) treatment of isolated rat cardiac mitochondria produced a marked decrease of both mitochondrial flavin adenine dinucleotide (FAD)- and nicotinamide adenine linked respiratory control indices (p < 0.001). Enzymatic assays of the mitochondrial electron transport chain (complexes I–V) and the mitochondrial matrix marker enzyme citrate synthase, showed marked concentration-dependent impairment in activity and integrity following exposure to domoic acid (p < 0.01). Similar mitochondrial effects were seen following exposure to the glutamic acid analog, kainic acid (0.5–2µM). Domoic acid (0.05–10µM; 40 min) was shown by competitive enzyme-linked immunosorbent assay to traverse the cellular membrane of H9c2 rat cardiac myoblasts. Exposure of intact H9c2 cells to domoic acid (10µM; 24 h) impaired complex II–III activity but did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid (0.05–5µM). This is the first study to demonstrate a direct effect of domoic acid on cardiac mitochondrial energetics. However, the absence of substantial damage to intact cardiomyocytes raises questions regarding direct toxicological effects on cardiac energetics or viability under conditions of natural domoic acid exposure.
Key Words: domoic acid; mitochondria; cardiac energetics; excitotoxins.
2 Current Address: Department of Neurology at UCLA, 635 Charles E Young Drive South, Neuroscience Research Building, Los Angeles, California 90095.
3 Current Address: School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A5C1.