Biomarkers of 3-Nitropropionic Acid (3-NPA)-Induced Mitochondrial Dysfunction as Indicators of Neuroprotection
| Autor: | Zbigniew Binienda, Robert L. Rountree, P.L. Nony, Andrew C. Scallet |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Convulsants Oxidative phosphorylation Pharmacology Neuroprotection General Biochemistry Genetics and Molecular Biology Body Temperature Rats Sprague-Dawley stomatognathic system History and Philosophy of Science medicine Animals chemistry.chemical_classification biology General Neuroscience Succinate dehydrogenase Neurotoxicity Brain Mitochondrial Myopathies Fatty acid Hypothermia Nitro Compounds medicine.disease Respiratory enzyme Rats Succinate Dehydrogenase Enzyme Biochemistry chemistry biology.protein Propionates medicine.symptom Biomarkers |
| Zdroj: | Annals of the New York Academy of Sciences. 939:381-392 |
| ISSN: | 1749-6632 0077-8923 |
| DOI: | 10.1111/j.1749-6632.2001.tb03647.x |
| Popis: | In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3-Nitropropionic acid (3-NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme important for mitochondrial energy production. We have been studying biomarkers of 3-NPA exposure in the expectation that such markers may be useful in the screening process to identify neuroprotective agents against neurotoxicity produced by mitochondrial energy dysfunction. Animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity and measurement of immediate postmortem rectal temperature. 3-NPA-treated rats experienced progressive hypothermia that reached a loss of 3 degrees C or more in core body temperature by three hours after dosing. The optical density of the SDH stain in brain was reduced, following a similar time course, most prominently in the cerebellum and least sharply in the thalamus. Some rats were given injections of L-carnitine (an enhancer of fatty acid transport) either alone, or as a pretreatment prior to a dose of 3-NPA. Although L-carnitine deficiency by itself can produce mitochondrial dysfunction, pretreatment with L-carnitine was of limited efficacy at overcoming the effects of 3-NPA on either body temperature or quantitative SDH histochemistry. Body temperature and SDH histochemistry may be useful biomarkers for evaluating the efficacy of neuroprotective agents against lower doses of 3-NPA, against other pharmacological models of mitochondrial dysfunction, or even against genetic mitochondrial diseases. |
| Databáze: | OpenAIRE |
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