Interictal and ictal activity in the rat cobalt/pilocarpine model of epilepsy decreased by local perfusion of diazepam.

Abstract

We investigated the efficacy of focal perfusion of diazepam (DZP) in reducing seizures produced by focal cobalt and systemic pilocarpine in the rat. Cobalt chloride crystals (3.5 mg/kg) were inserted stereotactically into the left hippocampus and recording electrodes affixed to the head of 23 rats. Focal spiking was evident within 5-7 days of implantation. Occasional ictal electrographic events were observed with cobalt alone, but consistent ictal events could be produced by intraperitoneal injection of pilocarpine hydrochloride (60 mg/kg) into the cobalt-treated animals. When rhythmical spiking was observed, the animals were treated either with DZP (0.25 mg in 50 microliters) or a vehicle (VEH) delivered into the left hippocampus. Blinded spike counts before and after injection showed spiking at 133.3 +/- 53.4% of baseline (mean +/- SD, n = 8) for the VEH-treated animals and 2.7 +/- 3.3% (n = 8) for the DZP-treated animals. Ictal events occurred in seven of the eight VEH-treated and two of the eight DZP-treated rats. Mean time to the first ictal event was 5.9 +/- 6.9 min for VEH-treated animals and 24 +/- 32.6 min for DZP-treated animals. DZP injected into the hippocampus contralateral to the cobalt did not reduce spiking. Systemic levels of DZP were unmeasurable in nine of ten tested animals. Focal perfusion of DZP therefore effectively reduced spiking in this cobalt chloride/pilocarpine model of focal and secondarily generalized epilepsy. This model, while involving GABAergic mechanisms, does not entirely depend upon GABAergic mechanisms. The findings therefore broaden the possibility of using focal DZP as a treatment for partial seizures.