Modulating P-glycoprotein regulation: future perspectives for pharmacoresistant epilepsies?

Abstract

Enhanced brain efflux of antiepileptic drugs by the blood-brain barrier transporter P-glycoprotein is discussed as one mechanism contributing to pharmacoresistance of epilepsies. P-glycoprotein overexpression has been proven to occur as a consequence of seizure activity. Therefore, blocking respective signaling events should help to improve brain penetration and efficacy of P-glycoprotein substrates. A series of recent studies revealed key signaling factors involved in seizure-associated transcriptional activation of P-glycoprotein. These data suggested several interesting targets, including the N-methyl-d-aspartate (NMDA) receptor, the inflammatory enzyme cyclooxygenase-2, and the prostaglandin E2 EP1 receptor. These targets have been further evaluated in rodent models, demonstrating that targeting these factors can control P-glycoprotein expression, improve antiepileptic drug brain penetration, and help to overcome pharmacoresistance. In general, the approach offers particular advantages over transporter inhibition as it preserves basal transporter function. In this review the different strategies for blocking P-glycoprotein upregulation, including their therapeutic promise and drawbacks are discussed. Moreover, pros and cons of the approach are compared to those of alternative strategies to overcome transporter-associated resistance. Regarding future perspectives of the novel approach, there is an obvious need to more clearly define the clinical relevance of transporter overexpression. In this context current efforts are discussed, including the development of imaging tools that allow an evaluation of P-glycoprotein function in individual patients.