GABA uptake blocker NNC-711 exhibits marked anticonvulsant action in two cortical epileptic models in immature rats.

Abstract

To study the anticonvulsant action of a gamma-aminobutyric acid (GABA) uptake inhibitor NNC-711 in two models of cortical epileptogenesis in immature rats. Twelve-, 18-, and 25-day-old rat pups with implanted electrodes were used in this study. Epileptogenic foci were elicited by a local application of bicuculline methiodide (BMI) on the sensorimotor cortical region by means of an implanted cannula, and cortical epileptic afterdischarges (ADs) were induced by low-frequency stimulation (8 Hz) of the same cortical area. Epileptogenic foci were formed after pretreatment with NNC-711 (1 or 10 mg/kg, i.p.), and epileptic ADs were elicited in the second experimental series. Then NNC-711 was administered in the same doses, and stimulation was repeated. NNC-711 did not block the formation of epileptogenic foci, but it significantly suppressed the spontaneous transition of interictal focal into ictal activity in all age groups. The intensity of movements accompanying stimulation of the sensorimotor cortex was less under the influence of NNC-711 in the 18- and 25-day-old rats. The duration of cortical ADs was shortened in all age groups, but transient abolition of ADs was observed only after the higher dose in the 25-day-old rats. In addition, the intensity of clonic seizures appearing during ADs decreased, and the transition of ADs into another type due to an involvement of limbic structures failed to appear in the 18- and 25-day-old rats. Primary epileptogenesis in the cerebral cortex was hardly influenced by NNC-711, but the spread of epileptic activity was markedly suppressed. This effect was better expressed in the 18- and 25-day-old animals than in the youngest group.