Abstracts

Rationale: To determine the anticonvulsant properties of the antiepileptic drug vigabatrin (VGB) in the treatment of lithium-pilocarpine (Li-Pi) and the cobalt-homocysteine (Co-Ho) rat models of status epilepticus (SE). Methods: Male Sprague-Dawley rats had epidural screw electrodes implanted in the skull for EEG recording. Two models of SE were tested, the first induced by intraperitoneal (IP) injection of lithium chloride (3 mmol/kg) followed by subcutaneous (SC) injection of pilocarpine (30 mg/kg) 20-24 hrs later, and the second created by implanting cobalt 6mg in the left frontal region (F3 location) then inducing status by injecting homocysteine 5.5 mmol/kg IP 96-120 hours later. Following injection of pilocarpine or homocysteine, the EEG was monitored continuously. VGB solution was made by dissolving 300mg in normal saline. VGB monotherapy effect was tested at early SE, as well as at late refractory SE as a tertiary treatment following 0.1 mg/kg diazepam (DZM) and 0.25mg/kg phenobarbital (PB). Results: Early SE (SE EEG Stage I) was induced with Li-Pi in 4 groups of 3 rats. Each of these groups was treated with either 1000, 2000, 3000, or 4000mg/kg of VGB . No clear alteration in the progression through the 5 stages of SE was noted in these groups. Late SE (SE EEG Stage V) was induced with Li-Pi in 2 rats. VGB, 3000mg/kg, was given IP 10 minutes after DZM and PB. DZM/PB resulted in cessation of the clinical manifestation of SE as expected but without a clear alteration of the EEG findings, and the addition of VGB did not show a clear effect on the EEG findings. Both animals died within the following 36 hours. SE EEG Stage I was induced with Co-Ho in 2 rats. Both received VGB 3000mg/kg after reaching Stage I. Both animals progressed through the 5 stages of status epilepticus. In the first animal, SE stopped around 8 hours later and the rat survived, the other rat died 1 hour after the onset of the status. Further evaluation of the VGB effect of VGB in late stage Li-Pi-induced SE as well as early and late stages of Co-Ho SE is currently in progress. Conclusions: SE remains as one of the life-threatening neurological emergencies that is frequently difficult to treat. Therefore, there is a great need to develop new treatments for SE. VGB has been found to increase GABA concentration in the frontal cortex but not in the hippocampus. Thus we chose to study two models of SE: a "cortical" model (Co-Ho) and a "hippocampal" model (Li-Pi). The preliminary results so far show that VGB has no effect on the early or late (Li-Pi) SE. This might be due to the fact that the maximum increase in GABA concentration has been reported to occur around 3 hours following VGB IP administration. Alternatively, VGB might have less effect on the "hippocampal" model of status epilepticus given that it has been shown to have no effect on GABA concentration in the hippocampus. This could explain why in one of the Co-Ho rats SE stopped and the rat survived. Further testing of the effect of VGB on the "cortical" model of SE is necessary and is currently in progress. This research was supported by a grant from Lundbeck, Inc.