The cationic anomalous inward rectifier current I_h has been suggested to be a pacemaker current controlling oscillatory activity in certain brain regions and recent evidence has proposed a role for this channel in epileptic states. We have therefore investigated whether I_h is critical in the generation of epileptiform discharges recorded from the adult hippcampal slice preparation, using extracellular electrophysiological techniques. The effect of the I_h blocker ZD-7288 was examined in a number of in vitro models of epileptiform activity, induced by a range of pharmacological manipulations.

Male Lister Hooded rats were humanely killed by cervical dislocation. Brain slices were prepared using standard methods and extracellular recordings were made from stratum pyramidale in hippcampal area CA3. Data are presented as mean ± S.E.M. ZD-7288 produced a concentration-dependent inhibition of both non-synaptic and synaptically-mediated epileptiform activity. Removing extracellular Ca²⁺ and elevating K⁺ to 6 mM resulted in epileptiform activity which is independent of action potential driven synaptic activity. This non-synaptic bursting was partially inhibited by 10 µM ZD-7288 (32 ± 8 % reduction; n = 5) and completely abolished by 100 µM ZD-7288 (n = 5). Similarly, ZD-7288 produced a concentration-dependent inhibition of synaptically-mediated epileptiform activity in the following experimental models: removal of extracellular Mg²⁺ (IC₅₀ = 23 ± 4 µM; n = 6), elevation of extracellular K⁺, from 3 to 8.5 mM (IC₅₀ = 27 ± 7 µM; n = 3-11) and the addition of 10 µM bicuculline to the extracellular medium (IC₅₀ = 18 ± 7 µM; n = 5). It has recently been reported that prolonged ZD-7288 application exerts a non-specific depression of glutamatergic synaptic transmission. Therefore we compared the time course of ZD-7288 inhibition of fEPSPs (recorded in area CA3 in response to stimulation in the dentate hilus) and epileptiform bursting induced by 10 µM bicuculline. At 30 and 60 mins after 100 µM ZD-7288 application a significant reduction in bursting frequency was observed without any significant change in fEPSP amplitude. A clear reduction in fEPSP amplitude was only observed after 120 mins, by which time epileptiform bursting had been abolished. Furthermore, capsazepine which exhibits similar potency to ZD-7288 at inhibiting I_h, failed to inhibit glutamatergic synaptic transmission per se (100 µM) but produced a significant inhibition of bicuculline-induced epileptiform activity (61 ± 8% n = 7 at 10 µM).

These data suggest that broad spectrum inhibition of I_h reduces neuronal hyperexcitability in the hippocampus and that molecules possessing this profile may be useful in treating temporal lobe epilepsy.