AMPA/kainate-related mechanisms contribute to convulsant and proconvulsant effects of 3-nitropropionic acid.
The role of the glutamatergic system in the convulsant and proconvulsant action of a mitochondrial toxin, 3-nitropropionic acid, was studied in mice. The occurrence of 3-nitropropionic acid-induced seizures was inhibited by the alpha-amino-2,3-dihydro-5-methyl-3-oxo-isoxazole-propionate (AMPA)/kainate receptor antagonists, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione disodium (NBQX) and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine HCI (GYKI 52466), with ED50 of 14.1 (7.9-25.2) and 7.2 (5.3-9.6) mg/kg, respectively. The N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonic acid (CPPene), were ineffective. Moreover, 3-nitropropionic acid given in a subthreshold dose potently enhanced seizures generated by intracerebroventricular administration of AMPA and kainate, lowering their CD50 from 0.98 (0.83-1.17) and 0.73 (0.64-0.83) to 0.55 (0.45-0.66) (P<0.001) and 0.58 (0.51-0.65) (P<0.05) nmol, respectively. In contrast, NMDA action was not changed by 3-nitropropionic acid application. We conclude that AMPA/kainate-mediated events are involved in proconvulsive and convulsive effects of 3-nitropropionic acid.
Urbanska
E M
EM
Department of Pharmacology and Toxicology, Medical University School, Lublin, Poland. ewau@galen.imw.lublin.pl
Blaszczak
P
P
Saran
T
T
Kleinrok
Z
Z
Turski
W A
WA
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009574:Nitro Compounds; D011422:Propionates; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D016202:N-Methylaspartate; C015392:3-nitropropionic acid