Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats

Abstract

Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the epileptic focus region and to be one cause of intractable epilepsy. To reach further proof for this multidrug transporter hypothesis, we compared P-glycoprotein expression rates in subgroups of Wistar rats which are sensitive or resistant to the anticonvulsant effect of the antiepileptic drug phenytoin in the amygdala-kindling model of temporal lobe epilepsy. In the electrode-implanted amygdala of phenytoin-resistant rats, the area labelled for P-glycoprotein was more than twice as large than that in phenytoin-sensitive rats. The data indicate that P-glycoprotein expression levels in the kindled focus have a critical impact on the anticonvulsant response to antiepileptic drugs.

Targeting Prostaglandin E2 EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation

“…However, it is a matter of an ongoing debate whether transporter overexpression contributes to pharmacoresistance (Löscher and Sills, 2007). Experimental key findings, including studies that describe a correlation among increased P-glycoprotein expression, reduced antiepileptic drug brain penetration, and limited drug efficacy indicate that P-glycoprotein plays a critical role in antiepileptic pharmacotherapy (Rizzi et al, 2002;Potschka et al, 2004;van Vliet et al, 2007;Wen et al, 2008). Proof-of-principle for the transporter hypothesis in rodent models came from studies in which efficacy of the antiepileptic drugs phenobarbital or phenytoin was significantly improved by add-on treatment with a selective Pglycoprotein inhibitor (Brandt et al, 2006;van Vliet et al, 2006).…”

“…Kindling of mice and determination of initial kindling after-discharge thresholds by using an ascending stair-step procedure were performed as described previously for rats (Potschka et al, 2004;Pekcec et al, 2007). In 1-min intervals, the initial current of 8 A was increased in steps of approximately 20% of the previous current until after-discharges were elicited.…”

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

“…In both models, AED nonresponders exhibited a significantly higher Pgp expression in brain capillary endothelial cells than responders. 81,82 With respect to the fourth criterion of Sisodiya, 32 i.e., demonstration that inhibition or avoidance of the resistance-mediating mechanism counteracts drug resistance in epilepsy, we have some indirect evidence from experiments with diverse AEDs in pharmaco-resistant rats selected from the kindling model of TLE. 83 All AEDs that were substrates for Pgp showed absent or low anticonvulsant efficacy in nonresponders that had been selected by repeated testing with the AED phenytoin.…”

The Blood-Brain Barrier in Epilepsy

“…Moreover, recent in vivo data, including our own studies, demonstrate that P-gp does limit AEDs from entering the brain (Brandt et al, 2006;Liu et al, 2007;Van Vliet et al, 2007). Using a drug-resistant epilepsy rat model, Potschka et al showed that animals not responding to phenytoin exhibited 2-fold higher P-gp expression levels in brain capillaries compared to animals responding to treatment (Potschka et al, 2004). van Vliet et al demonstrated that inhibiting P-gp counteracted phenytoin resistance, which reduced seizure occurrence in rats (Van Vliet et al, 2006).…”