Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures.
Beta-N-Methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neonatal mouse cortex explants (EC100 = 28 microM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphono-heptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species.(ABSTRACT TRUNCATED AT 250 WORDS)
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000409:Alanine / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000599:Amino Acids, Diamino / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D046508:Culture Techniques; D000087522:Cyanobacteria Toxins; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008815:Mice, Inbred Strains; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009994:Osmolar Concentration; D010875:Pipecolic Acids / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000596:Amino Acids; D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D009498:Neurotoxins; D010875:Pipecolic Acids; C001824:beta-N-methylamino-L-alanine; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; C029262:2,3-piperidinedicarboxylic acid; D015763:2-Amino-5-phosphonovalerate; D000409:Alanine; C031231:2-amino-7-phosphonoheptanoic acid