Superfusion of verapamil on the cerebral cortex does not suppress epileptic discharges due to restricted diffusion (rats, in vivo)

Abstract

The organic calcium channel blocker verapamil has been demonstrated to block epileptic activity in various experimental models both in vitro and in vivo. The drug, however, does not pass the blood-brain barrier, so that both the oral route and intravenous administration of the drug are ruled out for antiepileptic treatment. The present investigations analyzed the effects of verapamil applied epicortically in experimental models of interictal penicillin-induced and ictal pentylenetetrazol-induced epileptic activity in rats. Such epicortical application of verapamil was ineffective in suppressing either interictal or ictal epileptic activity. To test whether this lack of effect was due to poor penetration of the substance into the cortical tissue, the diffusion characteristics of verapamil were studied in agar and in gray matter by pressure microejection and an appropriate verapamil-selective microelectrode. The diffusion could be described fully by a diffusion coefficient D (5.08 × 10 −6cm 2·s −1), tortuosity ψ (1.51) and concentration-dependent uptake k′ (2.23 × 10 −3s −1). Using these values, the depth-dependent concentration gradient resulting from superfusion of the substance was calculated for agar and brain. In concentration measurements done in brain tissue, however, verapamil could not be detected in cortical layers deeper than 150 μm, which did not agree with the theoretical prediction. This observation may indicate a diffusion barrier at the interface between superfusing fluid and tissue. The results indicate that epicortical administration of verapamil is not efficacious in treatment of epilepsy.