Biochemical and neurotoxicological effects of L-2-chloropropionic acid on rodent brain

L-2-Chloropropionic acid (L-CPA) is selectively toxic to cerebellar granule cells; necrosis is first observed in rats 36 h after L-CPA administration (750 mg/kg p.o.) and becomes marked by 48 h. L-CPA has also been shown to a ctivate the mitochondrial pyruvate dehydrogenase (PDH) complex in fasted ad ult rats, resulting in reduced blood glucose and lactate levels. This study aimed to investigate the biochemical and neurotoxicological effects of L-C PA on the brain. Extracts, prepared from guinea-pig cerebellar and cerebral cortex slices incubated in the presence of L-CPA, were analysed using H-1 magnetic resonance spectroscopy, P-31 magnetic resonance spectroscopy, and amino acid analysis. Glucose metabolism was studied by monitoring the metab olism of [1-C-13]glucose using gas chromatography/mass spectrometry, Increa sed glucose metabolism and decreases in the pool sizes of lactate and alani ne were observed in both tissues, demonstrating activation of the PDH compl ex, Extracts were also prepared from the forebrain and cerebellum of animal s that had been treated in vivo with L-CPA and analysed as described for th e in vitro studies. Similar evidence for PDH activation was demonstrated at 2 and 24 h after dosing in both tissues. At 48 h after dosing, when signs of toxicity are observed, an increase in the lactate concentration and a de crease in N-acetylaspartate in the cerebellum but not in the forebrain conf irmed the selective neurotoxic action of L-CPA. These results suggest that activation of the PDH complex does not directly lead to the delayed selecti ve neurotoxicity of L-CPA.