Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy

Abstract

Epidemiological data indicate that 20-40% of the patients with epilepsy are refractory to treatment with antiepileptic drugs (AEDs). The mechanisms underlying pharmacoresistance in epilepsy are unclear, but several plausible hypotheses have emerged, including loss of AED target sensitivity in the epileptic brain, decreased AED concentrations at brain targets because of localized overexpression of drug efflux transporters in epileptogenic brain tissue, and network alterations in response to brain damage associated with epilepsy. Rat models of epilepsy in which part of the animals are resistant to treatment with AEDs offer a means to investigate the mechanisms underlying AED resistance. In the present study, AED-responsive and AED-resistant rats were selected from a model in which spontaneous recurrent seizures develop after a status epilepticus induced by electrical stimulation of the basolateral amygdala. For selection into responders and nonresponders, epileptic rats were treated over two weeks by phenobarbital. Subsequent histological examination showed neurodegeneration of the CA1, CA3 and dentate hilus in only one of eight responders but five of six nonresponders (P=0.0256). Based on previous studies in AED-resistant rats of this model, we hypothesized that changes in the structure and function of inhibitory GABA(A) receptors may contribute to drug resistance. We therefore analyzed the distribution and expression of several GABA(A) receptor subunits (alpha1, alpha2, alpha 3, alpha 4, alpha 5, beta2/3, and gamma 2) immunohistochemically with specific antibodies in the hippocampal formation of responders, nonresponders and nonepileptic controls. In nonresponders, decreased subunit staining was observed in CA1, CA2, CA3, and dentate gyrus, whereas much less widespread alterations were determined in responders. Furthermore, upregulation of the alpha 4-subunit was observed in the CA1 of nonresponders. Our data suggest that alterations in GABA(A) receptor subtypes may be involved in resistance to AEDs.