Neuroprotective effects of MK-801 on L-2-chloropropionic acid-induced neurotoxicity

L-2-Chloropropionic acid is selectively toxic to the cerebellum in rats; th e granule cell necrosis observed within 48 h can be prevented by prior admi nistration of MK-801. Short-term treatment (2 h) with L-2-chloropropionic a cid has also been shown to activate the mitochondrial pyruvate dehydrogenas e complex in fasted adult rats. This study aimed to investigate the effect of prior exposure to MK-801 on the biochemical and neurotoxicological effec ts of L-2-chloropropionic acid. Extracts were prepared from the forebrain a nd cerebellum of animals that had been treated with L-2-chloropropionic aci d, with and without prior treatment with MK-801, and were analysed using ma gnetic resonance spectroscopy and amino acid analysis. Glucose metabolism w as studied by monitoring the metabolism of [1-C-13]-glucose using GC/MS. L- 2-Chloropropionic acid caused increased glucose metabolism in both brain re gions 6 h after administration, confirming activation of the pyruvate dehyd rogenase complex, which was not prevented by MK-801. After 48 h an increase in lactate and a decrease in N-acetylaspartate was observed only in the ce rebellum, whereas phosphocreatine and ATP decreased in both tissues. MK-801 prevented the changes in lactate and N-acetylaspartate, but not those on t he energy state. These studies suggest that L-2-chloropropionic acid-induce d neurotoxicity is only partly mediated by the NMDA subtype of glutamate re ceptor.