Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus.
OBJECTIVE
More than one third of patients with epilepsy have inadequate control of seizures with drug therapy, but mechanisms of intractability are largely unknown. Because of this large number of pharmacoresistant patients with epilepsy, the existing process of antiepileptic drug (AED) discovery and development must be reevaluated with a focus on preclinical models of therapy-resistant epilepsy syndromes such as mesial temporal lobe epilepsy (TLE). However, although various rodent models of TLE are available, the pharmacoresponsiveness of most models is not well known. In the present study, we used a post-status epilepticus model of TLE to examine whether rats with spontaneous recurrent seizures (SRSs) differ in their individual responses to phenobarbital (PB).


METHODS
Status epilepticus was induced in Sprague-Dawley rats by prolonged electrical stimulation of the basolateral amygdala. Once the rats had developed SRSs, seizure frequency and severity were determined by continuous EEG/video recording over a 6-week period (i.e., a predrug control period of 2 weeks, followed by PB treatment for 2 weeks, and a postdrug control period of 2 weeks). PB was administered twice daily at maximal tolerated doses.


RESULTS
Analysis of plasma drug concentrations showed that drug concentrations within the therapeutic range (10-40 microg/ml) were maintained in all rats throughout the period of treatment. In six (55%) of 11 rats, complete control of seizures was achieved, and another rat exhibited a >90% reduction of seizure frequency. These seven rats were considered responders. The remaining four (36%) rats showed either no response at all (n=3) or only moderate reduction in seizure frequency and were therefore considered nonresponders. Plasma drug concentrations did not differ between these two groups of rats.


CONCLUSIONS
These data demonstrate that, similar to patients with epilepsy, rats with SRSs markedly differ in their individual responses to AED treatment. Pharmacoresistant rats selected by prolonged drug treatment from groups of rats with SRSs may provide a unique model to study mechanisms of pharmacoresistance and to identify novel AEDs for treating seizures of patients currently not controlled with existing therapies.
Brandt
Claudia
C
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Volk
Holger A
HA
Löscher
Wolfgang
W
D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000706:statistics & numerical data; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects; D008991:Monitoring, Physiologic / Q000706:statistics & numerical data; D010634:Phenobarbital / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000209:etiology / Q000503:physiopathology*; D014743:Videotape Recording
D000927:Anticonvulsants; D010634:Phenobarbital