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Neuroprotective effects of MK‐801 on l ‐2‐chloropropionic acid‐induced neurotoxicity
Author(s) -
Williams R. E.,
Lock E. A.,
Bachelard H. S.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00104.x
Subject(s) - biology , neurotoxicity , medicine , glutamate receptor , endocrinology , cerebellum , phosphocreatine , metabolism , biochemistry , receptor , toxicity , energy metabolism
l ‐2‐Chloropropionic acid is selectively toxic to the cerebellum in rats; the granule cell necrosis observed within 48 h can be prevented by prior administration of MK‐801. Short‐term treatment (2 h) with l ‐2‐chloropropionic acid has also been shown to activate the mitochondrial pyruvate dehydrogenase complex in fasted adult rats. This study aimed to investigate the effect of prior exposure to MK‐801 on the biochemical and neurotoxicological effects of l ‐2‐chloropropionic acid. Extracts were prepared from the forebrain and cerebellum of animals that had been treated with l ‐2‐chloropropionic acid, with and without prior treatment with MK‐801, and were analysed using magnetic resonance spectroscopy and amino acid analysis. Glucose metabolism was studied by monitoring the metabolism of [1‐ 13 C]‐glucose using GC/MS. l ‐2‐Chloropropionic acid caused increased glucose metabolism in both brain regions 6 h after administration, confirming activation of the pyruvate dehydrogenase 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 cerebellum, whereas phosphocreatine and ATP decreased in both tissues. MK‐801 prevented the changes in lactate and N ‐acetylaspartate, but not those on the energy state. These studies suggest that l ‐2‐chloropropionic acid‐induced neurotoxicity is only partly mediated by the NMDA subtype of glutamate receptor.