Comparison of the Chronic Anticonvulsant Activity and Safety of IEM-2062, Sodium Valproate, and Memantine in a Corasol Kindling Model in Rats

Abstract

Chronic oral administration of IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], which produces combined blockade of NMDA and AMPA receptors, at a dose of 3 mg/kg was found to induce a maximal anticonvulsant effect in rats with corasol kindling, producing a 100% decrease in the number of rats demonstrating corasol kindling and a 3.3-fold reduction in the mean severity of clonic-tonic kindled seizures. IEM-2062 induced significant anticonvulsant effects over a wide range of doses (1–48 mg/kg), which was 22–24 times greater than that of memantine (12–20 mg/kg) and sodium valproate (100–200 mg/kg). Sodium valproate and memantine induced significant impairment to movement activity in an open field at the doses having maximal anticonvulsant effects in rats with corasol kindling. At the same time, IEM-2062 induced impairments to movement activity only at a very high dose, 92 mg/kg, which was 30.7 times greater than the dose producing the maximal anticonvulsant effect in rats with corasol kindling. Thus, IEM-2062 decreases the severity of kindled seizures 1.7–1.9 times more effectively than sodium valproate and memantine, and has a range of therapeutic doses 22–24 times wider, as well as a 30.7 times greater level of safety than sodium valproate and memantine.