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Keywords:

  • Pharmacoresistance;
  • Antiepileptic drugs;
  • Intractable epilepsy;
  • P-glycoprotein;
  • Proconvulsant;
  • Status epilepticus

Summary: Purpose: Most patients who are resistant to the first antiepileptic drug (AED) treatment are also resistant to a treatment with a second or third AED, indicating that patients who have an inadequate response to initial treatment with AEDs are likely to have refractory epilepsy. Animal models of refractory epilepsy are important tools to study mechanisms of AED resistance and develop new treatment strategies for counteracting resistance. We have recently described a rat model of temporal lobe epilepsy (TLE), in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. Prolonged treatment of epileptic rats with phenobarbital (PB) resulted in two subgroups, PB responders and PB nonresponders.

Methods: In the present study we examined if rats with PB-resistant seizures are also resistant to phenytoin (PHT), using continuous EEG/video recording of spontaneous seizures.

Results: First, a new group of 15 epileptic rats was produced and selected by treatment with PB into responders (8 rats) and nonresponders (6 rats), respectively. During subsequent treatment with PHT, the doses of PHT had to be individually adjusted for each rat to avoid toxicity. Treatment with PHT led to complete seizure control in two animals and a >50% reduction of seizure frequency in three other rats, which were considered PHT responders. In nine of the remaining rats, PHT did not exert any clear anticonvulsant effect, so that these rats were considered nonresponders. Plasma levels of PHT did not differ significantly between responders and nonresponders. When comparing the PB and PHT nonresponder groups, five of the six PB-resistant rats (83%) were also resistant to PHT, demonstrating that rats that have an inadequate response to initial treatment with PB are likely to be also resistant to treatment with a second AED.

Conclusions: The AED-resistant rats of our model meet the definition of pharmacoresistance in animal models, that is, persistent seizure activity not responding to at least two AEDs at maximum tolerated doses. This new model of pharmacoresistant TLE may be useful in the targeted development of new therapies for refractory epilepsy.