Non-NMDA antagonists protect against kainate more than AMPA toxicity in the rat hippocampus.
Single focal injection of the excitatory amino acids (EAAs) kainic acid (KA, 1.1 nmol/microliters) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S)-AMPA, 6 nmol/microliters) into rat dorsal hippocampus resulted in widespread neurodegeneration with 90-100% loss of hippocampal pyramidal cells in CA1, CA2, CA3 and CA4 subfields, and 50-70% loss of dentate granule (DG) cells. Focal injection of NMDA (30 nmol/microliters) under the same conditions resulted in 70-90% loss of CA1 cells with less damage in CA2, CA3, CA4 and DG cells (30-50%, 10-30%, and 30-50%, respectively). The non-NMDA antagonists NBQX (2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f) quinoxaline) and GYKI 52466 (1-(amino)phenyl-4-methyl-7,8-methylendioxy-5H-2,3,benzodiazepine. HCl) co-injected (24 nmol/microliters) with EAAs or given as i.v. infusion (30 mg/kg/3h), protected against KA toxicity in CA1, CA2 and DG cells, with no protection in CA3 and CA4. NBQX i.v. protected against (S)-AMPA toxicity in the DG cells but no protection was observed against (S)-AMPA toxicity in hippocampal subfields (CA1, CA2 and CA4). Intravenous administration of NBQX and GYKI 52466 (30 mg/kg/3 h) also failed to protect against NMDA toxicity in the hippocampus. Systemic injections of D(-)-CPPene, (E)-4-(3-phos-phonoprop-2-enyl)-piperazine-2-carboxylic acid, (10 and 5 mg/kg, i.p., 20 min prior and 3 h post EAA injection) protected against NMDA and KA toxicity in the CA1, CA2 and DG subfield with no protective effect against (S)-AMPA toxicity.
Moncada
C
C
Department of Neurology, Institute of Psychiatry, London, U.K.
Arvin
B
B
Le Peillet
E
E
Meldrum
B S
BS
D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity*; D011712:Pyramidal Tracts / Q000187:drug effects* / Q000473:pathology; D011810:Quinoxalines / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D014151:Anti-Anxiety Agents; D009498:Neurotoxins; D011810:Quinoxalines; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid