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Received: I February 1999; Accepted: 11 May 1999
3-nitropropionic acid (3-NPA) is a toxin sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neurological disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme required for mitochondrial energy production. A single dose of 3-NPA (30 mg/kg S.C.) was given to singly-caged adult male Sprague-Dawley rats. Rectal temperature was measured after dosing as a potential biomarker of exposure to 3-NPA, and animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity. 3-NPA-treated rats experienced a progressive hypothermia, which reached a loss of 3[degrees]C or more in core body temperature by 3 hours after dosing. The optical density of the SDH stain in brain was reduced according to a similar time-course, most prominently in the cerebellum and least sharply in the thalamus. The caudate nucleus had the greatest density of SDH staining that we measured in brain; it also has been reported to be the region most consistently lesioned by 3-NPA. However, within other areas of brain such as subdivisions of the hippocampus, neither endogenous SDH activity nor its sensitivity to inhibition by 3-NPA could predict the susceptibility to neurodegenerative changes. Although SDH activity remained significantly reduced in most areas of brain (except thalamus) for up to 5 days after dosing, core temperatures had returned to control values by 5 days suggesting that animals can utilize an alternate method of heat production to withstand insult by 3-NPA.
INTRODUCTION
3-nitropropionic acid (3-NPA) is a chemical that contributes to the toxicity of various species of Astragalus, sometimes known as "locoweeds" or "milkweeds". After their consumption by livestock (James et al., 1980), lung and CNS lesions may occur, resulting in emphysema and locomotor dysfunction. Astragalus toxicity has been responsible for extensive economic losses in the ranching and cattle industries of the western United States. 3-NPA may also be formed by the fungus Arthrinium sp.; for example, an epidemic of acute encephalopathy in children that ate moldy sugarcane containing 3-NPA occurred recently in China (Ming, 1995). In vitro, 3-NPA inhibits cellular respiration by irreversible inactivation of succinate dehydrogenase (SDH), a mitochondrial Complex II enzyme responsible for the oxidation of succinate to fumarate in the...