Neuronal damage induced by beta-N-oxalylamino-L-alanine, in the rat hippocampus, can be prevented by a non-NMDA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline.
The neurotoxin beta-N-oxalylamino-L-alanine (BOAA), found in Lathyrus sativus seeds, is thought to be the causative agent of neurolathyrism. We have investigated the in vivo mechanism of action of BOAA by focal injection (1 microliter) in the dorsal hippocampus of male Wistar rats and comparing the pathological outcome with the effects of injections (1 microliter) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainate (KA) or N-methyl-D-aspartate (NMDA). Cellular damage induced by the excitatory amino acids in the pyramidal (CA1-CA4) and dentate granule neurones (DG) was assessed histologically 24 h after the injection. The study shows that BOAA (50 nmol) induces hippocampal toxicity with a highly selective pattern of regional cellular damage. The CA1, CA4 and DG subfields show 70-90% neuronal injury whereas CA2 and CA3 show only minimal damage. This pattern of cellular damage is similar to that induced by AMPA (1 nmol) and NMDA (25 nmol) but not KA (0.5 nmol). BOAA-induced neurotoxicity is prevented in a dose-dependent manner by focal co-injection of the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (1-25 nmol) but not by a dose of MK-801 (3 mg/kg i.p.) which is neuroprotective against an injection of NMDA. Delayed focal injections of NBQX (25 nmol) up to 2 h after the BOAA injection result in a significant protection of all pyramidal and granular cell regions. These results indicate that the in vivo hippocampal toxicity of BOAA is mediated by AMPA receptors rather than by KA or NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Willis
C L
CL
Department of Neurology, Institute of Psychiatry, Denmark Hill, London, UK.
Meldrum
B S
BS
Nunn
P B
PB
Anderton
B H
BH
Leigh
P N
PN
D000599:Amino Acids, Diamino; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity
D000599:Amino Acids, Diamino; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid