L-BOAA induces selective inhibition of brain mitochondrial enzyme, NADH-dehydrogenase.
Lathyrism, a human neurological disorder has been linked to the excessive consumption of a plant toxin, beta-oxalylamino-L-alanine (L-BOAA) present in Lathyrus sativus. The present study was carried out to elucidate the biochemical mechanisms underlying L-BOAA-induced toxic insult. Incubation of sagittal slices of mouse brain with L-BOAA resulted in dose and time-dependent inhibition of mitochondrial NADH-dehydrogenase (NADH-DH). Significant inhibition of NADH-DH was seen following incubation of brain slices with very low concentration of L-BOAA (0.1 pM). L-BOAA also induced lactate dehydrogenase (LDH) leakage from the slice into the medium in dose-dependent manner. The inhibition of NADH-DH preceded LDH leakage from the slices into the medium. L-BOAA had no effect on other mitochondrial enzymes, namely, isocitrate dehydrogenase or cytochrome c oxidase. Incubation of isolated mouse brain mitochondria with L-BOAA also resulted in inhibition of NADH-DH. L-BOAA-induced inhibition of NADH-DH was prevented by non-N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonists in general and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist (NBQX) in particular. Other glutamate agonists examined namely, N-methyl-D-aspartate, beta-N-methylamino-L-alanine (L-BMAA), L-glutamic acid, N-acetylaspartylglutamate (NAAG), quisqualic acid, kainic acid or AMPA did not have any effect on NADH-DH activity in slices although they induced LDH leakage from the slice into the medium. Incubation of brain slices with L-BOAA did not induce lipid peroxidation or changes in glutathione levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Pai
K S
KS
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Ravindranath
V
V
D000599:Amino Acids, Diamino; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D017470:Receptors, Glutamate / Q000187:drug effects; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000599:Amino Acids, Diamino; D017470:Receptors, Glutamate; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D007770:L-Lactate Dehydrogenase; D009245:NADH Dehydrogenase