The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model.
Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.
Smith
K A
KA
Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoeniz, AZ 85013, USA.
Fisher
R S
RS
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D004832:Epilepsy, Absence / Q000188:drug therapy*; D018756:GABA Antagonists / Q000494:pharmacology*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; C066430:CGP 35348; D002784:Cholesterol