Abstracts

Rationale: We have previously reported that the lamotrigine (LTG)-resistant kindled rat displays resistance to carbamazepine, phenytoin and topiramate but not valproate (Srivastava et al, Epilepsia. 44: 2003). This animal model may provide a unique system to evaluate novel antiepileptic drugs(AEDs). Since 1993, ten new AEDs have been introduced. Unfortunately, none of these drugs have exhibited a significant impact in the treatment of patients with intractable epilepsy. Levetiracetam (LEV) possesses a unique mechanism of action with proven efficacy against patients with partial seizures and in at least two animal models of pharmacoresistant seizures (the 6HZ partial psychomotor in mice and the PHT-resistant amygdala kindled rats. However, it does not display anticonvulsant effects in the traditional maximal electroshock and pentylenetetrazole seizure models. These observations support the hypothesis that new experimental models can identify novel AEDs with unique mechanism of action. The present study was thus aimed to evaluate the efficacy of LEV in LTG-resistant amygdala kindled rats.Methods: Two groups of male (n=8-10) Sprague Dawley rats were kindled via amygdala stimulation according to the method described by Postma et al, Epilepsia. 41: 2000. One hour before each kindling stimulation, rats in the control group received 0.5% methylcellulose and rats in the experimental group received LTG (5mg/kg, i.p.). Treatments were stopped once the control group were fully kindled. One day later, both groups were challenged with a higher dose of LTG (15 mg/kg, i.p.) to verify LTG- resistance in the experimental group (i.e., LTG- pretreated rats). The efficacy of LEV (50-100 mg/kg administered i.p. 60 min prior to kindling stimulation) was then evaluated in both LTG-sensitive and LTG-resistant groups. All animals were assessed for behavioral toxicity after LEV administration.Results: A fully kindled state (3 consecutive Racine stage 4-5 ) was established in both vehicle- and LTG-treated animals. Upon subsequent challenge with a higher dose of LTG, the fully kindled seizure of the vehicle-treated rats, but not the LTG-treated rats, was blocked by LTG. LEV displayed a significant anticonvulsant effect in both LTG-sensitive and LTG- resistant animals. LEV (100 mg/kg i.p) significantly blocked the expression of fully kindled behavioral seizures in both LTG- sensitive and LTG-resistant animals. In addition, LEV 100 mg/kg significantly reduced the after-discharge duration P≤0.05 in both the groups. No behavioral impairment was noted at either of the LEV doses tested.Conclusions: The present findings suggest that LEV is an effective AED in the LTG-resistant rat model of drug- resistant epilepsy. These results support further clinical studies of LEV in patients that are refractory to both first and second generation AEDs. These findings also support the use of the LTG-resistant, amygdala-kindled rat as a model of pharmaco-resistant epilepsy for the early identification of novel AEDs