Resistance to antiepileptic drugs and expression of P-glycoprotein in two rat models of status epilepticus

Abstract

Status epilepticus (SE) is a neurological emergency, characterized by continuous or intermittent seizures without full recovery of consciousness between seizures, which can result in death or neurological sequelae. In about one third of patients, SE is unresponsive to sequential treatment with first- and second-line antiepileptic drugs (AEDs). At least in part, this drug resistance may be due to AED target alterations induced by SE, such as reduced membrane expression of GABA(A) receptors. Apart from target alterations by receptor trafficking, SE is known to increase the brain expression of drug efflux transporters such as P-glycoprotein (Pgp), which might reduce concentrations of AEDs at their brain targets. However, it is not known whether overexpression of Pgp develops rapidly enough after onset of SE to be of any functional consequence for drug treatment. Therefore, we studied whether overexpression of Pgp at the blood-brain barrier is involved in refractory SE. Two rat SE models were used, the lithium/pilocarpine model and induction of SE by sustained electrical stimulation of the basolateral amygdala (BLA). Four AEDs, diazepam (DZP), phenobarbital (PB) and phenytoin (PHT) or fosphenytoin (FPHT) were administered at different times after onset of SE. In the pilocarpine model, once self-sustained SE was established, none of the AEDs alone was effective in terminating SE, but sequential injection of PB and DZP stopped SE. Administration of the Pgp inhibitor tariquidar did not prevent or counteract resistance to AEDs. In the BLA model, DZP and PB terminated SE in the majority of rats, whereas PHT or FPHT were ineffective. Immunohistochemical staining of Pgp did not indicate any increase of Pgp expression in brain capillary endothelial cells during SE, whereas significant overexpression was determined in both models 48 h after SE. The data suggest that, at least under the conditions of the present study, alterations in Pgp are not critically involved in refractory SE.