cgp-36742 and Epilepsy--Absence

Although the presence of functional GABAB receptors in mammalian brain has been known for more than 20 years, there is still only one therapeutic agent in use, baclofen, which mediates its effects directly via this receptor. However, activation of this receptor can produce numerous effects that might be amenable to drug development. Evidence from preclinical studies also suggests that antagonism of the GABAB receptor produces beneficial clinical effects.

Topics: Animals; Baclofen; Brain; Clinical Trials as Topic; Cognition; Drug Evaluation, Preclinical; Epilepsy, Absence; GABA Agonists; GABA Antagonists; Humans; Muscle Spasticity; Organophosphorus Compounds; Pain; Receptors, GABA-B; Substance-Related Disorders

The effects of combined and single administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3-benzodiazepine (LY 300164), and of the GABA(B) receptor antagonist gamma-aminopropyl-n-butyl-phosphinic acid (CGP 36742), on spontaneously occurring spike-wave discharges were investigated in WAG/Rij rats. LY 300164 had minor effects; only the highest dose (16 mg/kg) reduced the number of spike-wave discharges in a short time window. CGP 36742 was more effective as it significantly reduced the number of spike-wave discharges and shortened their duration at the doses of 25 and 100 mg/kg. The ED(50) values for the inhibition of spike-wave discharges by LY 300164 and CGP 36742 in a time window 30-60 min after injection were 15.5 and 16.6 mg/kg, respectively. The ED(50) of CGP 36742 was reduced to 8.0 mg/kg when this antagonist was administered in combination with LY 300164 (6 mg/kg). The interaction between the two antagonists appeared to be additive according to isobolographic analysis. Importantly, CGP 36742 and LY 300164 administered either alone or in combination had no apparent effects on behavior. These results may provide information for a rational approach to polytherapy for the treatment of generalized absence epilepsy.

Topics: Animals; Behavior, Animal; Benzodiazepines; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Epilepsy, Absence; Excitatory Amino Acid Antagonists; GABA Antagonists; GABA-B Receptor Antagonists; Male; Organophosphorus Compounds; Rats; Rats, Inbred Strains; Receptors, AMPA; Time Factors

A variety of animal models of absence epilepsy have been described and among these exists a genetically susceptible strain of rat (genetic absence epilepsy rats of Strasbourg (GAERS)). These rats produce periods of behavioural arrest with simultaneous production of cortical spike and wave discharges (SWD). GABAB receptor antagonists suppress completely the production of these spike and wave discharges. GABAB receptor ligands have also been reported to affect cognitive performance in rodents. The present study examined the cognitive performance of GAERS and the influence of GABAB receptor antagonists on this activity. Rats were injected intraperitoneally once per day with saline or a GABAB receptor antagonist (CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid) 100 mg/kg; CGP 56433 ([3-(1-(S)-[(3-(cyclohexylmethyl)hydroxy phosphinyl]-2-(S) hydroxy propyl] amino]ethyl]benzoic acid) ([3-{1-(S)-[{3-(cyclohexylmethyl)hydroxy phosphinyl]-2-(S) hydroxy propyl] amino]ethyl]benzoic acid) 1 mg/kg or CGP 61334 ([3-({[3-[(diethoxymethyl)hydroxy phosphinyl]propyl] amino}methyl]-benzoic acid (1 mg/kg). A two-way active avoidance test paradigm with negative reinforcement was used. Untreated GAERS performed significantly better than non-epileptic rats (P < 0.05) and this enhancement in cognitive performance was sustained in rats treated with the GABAB receptor antagonists.

Topics: Animals; Avoidance Learning; Benzoates; Epilepsy, Absence; GABA Antagonists; GABA-B Receptor Antagonists; Organophosphorus Compounds; Phosphinic Acids; Rats; Rats, Inbred Strains; Rats, Wistar; Reaction Time; Reinforcement, Psychology

In Wistar rats with spontaneous non-convulsive absence epilepsy, absence seizures were dose dependently suppressed by intraperitoneal administration of the GABAB receptor antagonists CGP 36742, 50-400 mg/kg, and CGP 56999, 0.25-0.75 mg/kg, and by bilateral microinjections of the same compounds into the lateral nuclei of the thalamus. In rats susceptible to audiogenic seizures, intraperitoneal administration of both GABAB receptor antagonists, at doses which suppressed absence seizures, facilitated the elicitation of sound-induced tonic seizures. In non-epileptic control rats, intraperitoneal injections of higher doses of CGP 36742 (800-2400 mg/kg) and CGP 56999 (3-6 mg/kg) induced delayed clonic convulsions, which were suppressed by pretreatment with baclofen. c-Fos protein was expressed after GABAB receptor antagonist-induced seizures in the cortex, hippocampus, amygdala, perirhinal and piriform cortex. Intra-cortical and hippocampal microinfusion of both GABAB receptor antagonists produced focal seizures. In conclusion, GABAB receptor antagonists suppress non-convulsive absence seizures by blocking thalamic GABAB receptors, while they induce convulsions in cortical and limbic structures.

Topics: Animals; Brain; Epilepsy, Absence; GABA Antagonists; GABA-B Receptor Antagonists; Male; Organophosphorus Compounds; Phosphinic Acids; Proto-Oncogene Proteins c-fos; Rats; Seizures