Molecular and Functional Alterations of P-Glycoprotein in a Genetic Model of Epilepsy: Insights from the Wistar Audiogenic Rat.

Abstract

Drug resistance remains a major challenge in epilepsy, and overexpression of ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), at the blood-brain barrier (BBB) has been consistently implicated in limiting central nervous system drug exposure. Genetic experimental models suitable for investigating molecular regulation and functional alterations of P-gp in epilepsy remain scarce. This study evaluated P-gp expression and functional alterations in the Wistar Audiogenic Rat (WAR), a genetic model of epilepsy exhibiting phenotypic heterogeneity. WAR animals were classified into refractory epilepsy (WAR-RE) or temporal lobe epilepsy (WAR-TLE) phenotypes and compared with non-epileptic Wistar controls. Fexofenadine, a well-established in vivo P-gp probe substrate, was administered orally, and plasma pharmacokinetic parameters were determined. P-gp expression at the BBB was assessed by immunohistochemistry in hippocampal regions. WAR-RE animals exhibited significantly increased systemic exposure to fexofenadine, characterized by higher area under the curve and prolonged half-life, alongside reduced apparent clearance, compared with control animals (< 0.05). In contrast, WAR-TLE animals showed greater interindividual variability without statistically significant differences. Immunohistochemical analysis revealed increased P-gp expression in hippocampal microvessels in both WAR phenotypes. These findings demonstrate that the WAR model displays molecular upregulation of P-gp at the BBB, accompanied by functional alterations in the disposition of a prototypical P-gp substrate. Although direct brain drug concentrations were not assessed, the integration of systemic pharmacokinetics with transporter expression supports the use of WAR as a genetic proof-of-concept model for studying P-gp regulation and transporter-mediated drug disposition in epilepsy. This model provides a valuable molecular framework for future investigations addressing transporter modulation and mechanisms underlying pharmacoresistance.