NEURONAL DAMAGE-INDUCED BY BETA-N-OXALYLAMINO-L-ALANINE, IN THE RAT HIPPOCAMPUS, CAN BE PREVENTED BY A NON-NMDA ANTAGONIST, -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 mul) in the dorsal hippocampus of male Wistar rats and c omparing the pathological outcome with the effects of injections (1 mu l) of a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainat e (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. Th e 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 onl y minimal damage. This pattern of cellular damage is similar to that i nduced 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 foca l co-injection of the non-NMDA receptor antagonist -dihydroxy-6-nitro- 7-sulfamoyl-benzo(F)quinoxaline (NBQX) (1-25 nmol) but not by a dose o f 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 th e BOAA injection result in a significant protection of all pyramidal a nd granular cell regions. These results indicate that the in vivo hipp ocampal toxicity of BOAA is mediated by AMPA receptors rather than by KA or NMDA receptors. Neurones in the rat hippocampus do not die immed iately when exposed to BOAA but via a delayed process involving sustai ned AMPA receptor activation. Excitotoxic processes acting via AMPA re ceptors may play a role in the chronic loss of motor neurones seen in amyotrophic lateral sclerosis.