Action of beta-N-oxalylamino-L-alanine on mouse brain NADH-dehydrogenase activity.
beta-N-Oxalylamino-L-alanine (L-BOAA), a non-protein neuroexcitatory amino acid present in the seeds of Lathyrus sativus (chickling or grass pea), is known to produce its neurotoxic effects by overstimulation of non-N-methyl-D-aspartate receptors, especially alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, at micromolar concentrations. It has recently been reported that L-BOAA selectively inhibits mitochondrial enzyme NADH-dehydrogenase (NADH-DH) in brain slices at subpicomolar concentrations. The present study finds that up to 4 mM concentrations of pure L-BOAA fail to inhibit NADH-DH activity in mouse brain homogenate and isolated brain mitochondria. Two known inhibitors (rotenone and 1-methyl-4-phenylpyridinium ion, MPP+) of this mitochondrial enzyme produced significant inhibition under identical conditions. NADH-DH inhibition was also not observed in the homogenate or mitochondria from the brains of animals systemically treated with convulsive doses of L-BOAA. Some inhibition (20-37%) of NADH-DH activity was observed in mouse brain slices incubated with 100-1,000 microM concentrations of L-BOAA for 1 h at 37 degrees C in an atmosphere of 95% O2 and 5% CO2, but the inhibition was nonselective, because the activity of another mitchondrial enzyme, succinic dehydrogenase, was similarly inhibited by L-BOAA. These results are in contrast with the report that L-BOAA inhibits mitochondrial NADH-DH selectively at subpicomolar concentrations. We suggest the observed nonselective NADH-DH inhibition in mouse brain slices treated with L-BOAA is caused by neuronal damage through an excitotoxic mechanism.
Sabri
M I
MI
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201, USA.
Lystrup
B
B
Roy
D N
DN
Spencer
P S
PS
D000375:Aging / Q000378:metabolism; D000599:Amino Acids, Diamino; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009245:NADH Dehydrogenase / Q000378:metabolism*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000599:Amino Acids, Diamino; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D007770:L-Lactate Dehydrogenase; D009245:NADH Dehydrogenase