CL 218-872 pretreatment and intervention block kainate-induced convulsions and neuropathology

Abstract

Two experiments were conducted to test the antiepileptic properties of CL 218-872, a triazolopyridizine reported to have anxiolytic and anticonvulsant effects without accompanying sedative and ataxic effects. In Experiment 1 pretreatment with CL 218-872, a recently synthesized and potent triazolopyridizine, reduced kainic acid-induced convulsions and subsequent neuropathology in rats given ip doses of 25 mg/kg or greater. CL 218-872 at doses of 50 mg/kg or greater was more effective than a high dose of diazepam (20 mg/kg) in blocking status epilepticus-like convulsions and the associated widespread neuropathological sequelae. Moreover, diazepam pretreatment was associated with a higher mortality rate than CL 218-872. In Experiment 2 the efficacy of intervention with 20 mg/kg diazepam was compared with that of 50 mg/kg CL 218-872 in suppressing ongoing convulsions and reducing subsequent brain damage following a convulsant dose of kainic acid. Although CL 218-872 and diazepam were equally effective behaviorally (i.e., in suppressing kainic acid-induced convulsions), CL 218-872 was superior in its ability to reduce subsequent neuropathology, especially in the hippocampus and neocortex. Because kainic acid has been suggested as a model for human status epilepticus, CL 218-872 may be a potentially therapeutic treatment for this disorder.