Abstracts

Despite the introduction of several new antiepileptic drugs (AEDs) since 1993, pharmacoresistant epilepsy continues to represent a significant clinical problem. In recent years, several models have been identified that display one or more characteristics of pharmacoresistance (e.g., the phenytoin-resistant kindled rat, the 6 Hz psychomotor seizure, and the low Mg²⁺ slice preparation). More recently, it has been demonstrated that treatment with lamotrigine (LTG) to prevent amygdala kindling acquisition leads to subsequent resistance to LTG (Postma et al., Epilepsia. 41(12): 1514-21, 2000). The present study was initiated to assess whether this phenomenon generalizes to pentylenetetrazol (PTZ) kindling and if so, then assess whether LTG-resistant PTZ-kindled rats display resistance to the widely employed AEDs carbamazepine and valproate.
Chemical kindling in male Sprague Dawley rats was induced by giving a subconvulsant dose of 30 mg/kg PTZ intraperitoneally (i.p.), every alternate day for 68 days. Animals were observed for 30 min and seizure activity scored according to a slightly modified Racine scale. An additional group of animals received 5 mg/kg of LTG i.p. one hour before every PTZ challenge. The treatment was stopped once the vehicle-treated animals were fully kindled. A higher dose of LTG was administered to both groups (vehicle- and LTG-treated) on the day following the last kindling session. Carbamazepine and sodium valproate were also evaluated in both groups. Except for PTZ (normal saline), all the antiepileptic drugs were suspended in methylcellulose and given i.p. All experiments were approved by the University of Utah IACUC.
A stable PTZ kindled state was established by the 68^th experimental day in both saline and LTG treated animals. Thus pretreatment with LTG (5mg/kg) did not affect kindling development. Acute treatment with LTG (15mg/kg) was found to block the fully kindled seizure of the vehicle-treated animals. In contrast, LTG (15mg/kg)was found to be ineffective against the fully expressed kindled seizure in animals that had received LTG during the kindling procedure.
Although effective in the vehicle kindled group, carbamazepine (20 mg/kg ) was ineffective in the LTG-resistant animals. In contrast, sodium valproate (300 mg/kg) effectively blocked the fully expressed kindled seizure in both vehicle-treated and LTG-resistant kindled rats.
The present findings suggest that early chronic dosing with the LTG during kindling acquisition is ineffective in preventing the development of kindling and more importantly leads to the subsequent development of pharmacoresistance to LTG and carbamazepine but not valproic acid. These findings suggest that the LTG-resistant kindled rat may serve as a model of pharmacoresistant epilepsy. Ongoing studies are evaluating the histomorphological changes in vehicle- and LTG-kindled animals and assessing the efficacy of other AEDs in this kindling model of pharmacoresistance.
[Supported by: NINDS contract NO1-NS-9-2313]