Neurotoxicity of beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) on cultured cortical neurons.
Recent studies have implicated the ingestion of the structurally related plant excitotoxins, beta-N-methylamino-L-alanine (BMAA), and beta-N-oxalylamino-L-alanine (BOAA), in the pathogenesis of two human motor system diseases, the amyotrophic lateral sclerosis-Parkinsonism-dementia complex of Guam (Guam ALS-PD), and lathyrism, respectively. We have investigated the toxicity of these amino acids on cultured mouse cortical neurons in the presence of physiological concentrations of bicarbonate (a required toxic cofactor for BMAA neurotoxicity). A 24 h exposure to 10 microM - 3 mM BMAA, or to 300 nM - 100 microM BOAA, induced, concentration-dependent neuronal degeneration without glial damage; the neurotoxic EC50 for BMAA was about 1 mM, and the EC50 for BOAA was about 20 microM. At high concentrations, both compounds destroyed essentially the entire neuronal population. Neurotoxicity also depended on exposure duration, with reduced injury at an exposure time of 1 h, and increased injury at an exposure time of 3 days. Despite the fact that ingestion of BMAA and BOAA both lead to motor system damage, previous studies have suggested that the two excitotoxins act primarily on different glutamate receptor subtypes: BMAA on N-methyl-D-aspartate (NMDA) receptors, and BOAA on non-NMDA receptors. Consistent with these studies, the neurotoxicity of high concentrations of BMAA was substantially attenuated by 1 mM D-amino-5-phosphonovalerate (D-APV), whereas BOAA neurotoxicity was less sensitive to D-APV but was attenuated by 2 mM kynurenate.(ABSTRACT TRUNCATED AT 250 WORDS)
Weiss
J H
JH
Department of Neurology, Stanford University Medical Center, CA 94305.
Koh
J Y
JY
Choi
D W
DW
D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000087522:Cyanobacteria Toxins; D006651:Histocytochemistry; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000378:metabolism*; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015091:beta-Alanine / Q000633:toxicity
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C001824:beta-N-methylamino-L-alanine; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D009247:NADH, NADPH Oxidoreductases; D009252:NADPH Dehydrogenase