Neuroprotective effects of MK-801 on L-2-chloropropionic acid-induced neurotoxicity.
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.
Williams
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Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK. Becky.Williams@syngenta.com
Lock
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Bachelard
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D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002247:Carbon Isotopes; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004734:Energy Metabolism / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D018737:Hand Strength; D006843:Hydrocarbons, Chlorinated; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011422:Propionates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016548:Prosencephalon / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D000596:Amino Acids; D002247:Carbon Isotopes; D006843:Hydrocarbons, Chlorinated; D018696:Neuroprotective Agents; D011422:Propionates; D001224:Aspartic Acid; D019344:Lactic Acid; D016291:Dizocilpine Maleate; C000179:N-acetylaspartate; C021974:2-chloropropionic acid; D005947:Glucose; D003401:Creatine