KAINIC ACID-INDUCED SEIZURES AND BRAIN-DAMAGE IN THE RAT - DIFFERENT EFFECTS OF NMDA-RECEPTOR AND AMPA-RECEPTOR ANTAGONISTS

We have studied the effect of two glutamate receptor antagonists on se izures and hippocampal neurone loss in the rat after systemic kainic a cid administration. Intraperitoneal injection of the novel AMPA lpha-a mino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxalin-2,3-dione) (30 mg/kg x 3 and 15 mg/kg x 3) administered 30 and 15 min. before and simultaneous ly with injection of kainic acid (5 mg/kg) intraperitoneally, dramatic ally enhanced the toxicity of kainic acid leading to death of all anim als. When the NBQX dose was reduced to 8 mg/kg x 3, all animals surviv ed and neurone damage in the hippocampus did not differ from control a nimals. When NBQX (30 mg/kg x 3) was administered 30 - or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone lo ss. Post-kainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min, after intr aperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely p revented. The results emphasize the importance of the NMDA-receptor ac tivation for seizure generation and subsequent brain damage after intr aperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral isc haemia and hypoglycaemia, conditions which are also characterized by g lutamate-mediated damage. One possible explanation of the lowered seiz ure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal ce lls.