Enhancement of anti-absence effects of ethosuximide by low doses of a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist in a genetic animal model of absence epilepsy.
N-Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has been demonstrated to antagonize generalized tonic-clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA receptor antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients.
Russo
Emilio
E
Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University of Catanzaro, Catanzaro, Italy.
Citraro
Rita
R
De Fazio
Salvatore
S
Marra
Rosario
R
Gitto
Rosaria
R
Chimirri
Alba
A
De Sarro
Giovambattista
G
Di Paola
Eugenio Donato
ED
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects*; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000235:genetics*; D005013:Ethosuximide / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage
C470657:2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; D000927:Anticonvulsants; D018091:Receptors, AMPA; D044005:Tetrahydroisoquinolines; D005013:Ethosuximide; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid