Billion-fold difference in the toxic potencies of two excitatory plant amino acids, L-BOAA and L-BMAA: biochemical and morphological studies using mouse brain slices.
Plant amino acids beta-N-oxalylamino-L-alanine (L-BOAA, present in Lathyrus sativus) and beta-N-methylamino-L-alanine (L-BMAA, present in Cycas circinalis) have been implicated in the pathogenesis of human neurological disorders lathyrism and amyotrophic lateral sclerosis-Parkinson's dementia complex of Guam (ALS-PD), respectively. In view of the conflicting reports that have emerged on the role of L-BMAA in ALS-PD, we reinvestigated the comparative toxicity of L-BMAA and L-BOAA. We report here the potent toxicity of L-BOAA as examined in an in vitro model consisting of sagittal slices of mouse brain. Incubation of sagittal slices of mouse brain with L-BOAA (1 pM) resulted in significant leakage of lactate dehydrogenase (LDH) and potassium from the slices into the medium. Under similar conditions, L-BMAA-induced LDH leakage from the slices into the medium was observed only at very high concentration of the toxin, namely 1 mM. N-Methyl-D-aspartate (NMDA) receptor antagonists ameliorated the toxic effects of L-BMAA, while non-NMDA receptor antagonists (quinoxalinediones) protected against the toxicity of L-BOAA. Incubation of slices with L-BOAA for 1 h resulted in extensive vacuolation and degeneration of neurons in the thalamus and brain stem, and to a lesser extent in the hippocampus and cerebellar nuclei. The large sized neurons appeared to be affected to a greater extent than the smaller ones. The neurons in other areas of the brain also revealed variable degree of degeneration with swelling of axons and dendrites.(ABSTRACT TRUNCATED AT 250 WORDS)
Pai
K S
KS
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Shankar
S K
SK
Ravindranath
V
V
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D000087522:Cyanobacteria Toxins; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D006651:Histocytochemistry; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009498:Neurotoxins / Q000633:toxicity*; D016612:Paraffin Embedding; D010944:Plants / Q000737:chemistry*; D011188:Potassium / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000633:toxicity
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D011810:Quinoxalines; C001824:beta-N-methylamino-L-alanine; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007770:L-Lactate Dehydrogenase; D011188:Potassium