The complexity of roles of P-glycoprotein in refractory epilepsy: Pharmacoresistance, epileptogenesis, SUDEP and relapsing marker after surgical treatment

Alberto Lazarowski,Liliana Czornyj,Luisa Rocha

doi:10.5599/admet.3.2.162

Abstract

As described initially from clinical and experimental studies, P-glycoprotein (P-gp) plays a central role in the pharmacoresistance of epilepsy, acting by efflux of AEDs mainly at blood brain barrier (BBB) level. However, repetitive seizures can produce both brain and heart P-gp overexpression. Because P-gp activity induces membrane depolarization, its neuronal expression could be acting in the intrinsic mechanism of epileptogenesis, and its heart expression, can be a high risk factor of death, after severe-continuo convulsive stresses as in fatal status epilepticus or in SUDEP. Additionally, because P-gp is also a stem cell marker, we suggests that its constitutive overexpression in dysplastic neurons from brain epileptogenic areas observed in patients with refractory epilepsies, should be addressed as a risk factor of seizures relapse after surgical treatment. Here we discuss these concepts, based on our own clinical and experimental experiences, and reviewing the current literature on these subjects.

Highlights

P-glycoprotein; membrane depolarization; drug resistance; Sudden Unexpected Death in Epilepsy (SUDEP), biomarker, long-term relapse “What is a seizure and what is epilepsy?”
Epilepsy is the second most common neurological disorder after cerebrovascular accident (CVA) or stroke, and it is estimated that approximately ~1.0-2.0 % of the population is affected by different forms of epilepsy
It is important to distinguish between the truly drug-transporter properties of these proteins leading to the pharmacoresistant phenotype, from those related with plasmatic membrane depolarization inducing pro-epileptic effects, directly related with epileptogenesis as described for P-gp

Summary

Introduction

P-glycoprotein; membrane depolarization; drug resistance; SUDEP, biomarker, long-term relapse “What is a seizure and what is epilepsy?”. The questions are how so different factors and cellular/molecular process underlying during brain injury, can induce an enduring phenomenon with chronically recurrent seizures and why persistent (without control) convulsive stress is a main risk factor of develop pharmacoresistant epilepsy?

Results

Conclusion