GIRARDI Elena Silvia
Multidrug-resistance (MDR) proteins develops refractory epilepsy phenptype: clinical and experimental evidences. Review.
LAZAROWSKI A, CZORNYJ L, LUBIENIECKI F, VAZQUEZ S, D´GIANO C, SEVLEVER G, TARATUTO A, BRUSCO A, GIRARDI E.
Current drugs Therapy
Benthan Science Publisher
Lugar: Estados Unidos; Año: 2006 vol. 1 p. 291 - 291
Abstract Epilepsy affects approximately 3% of the population. Majority of epileptic patients may control their crisis with anticonvulsant drugs, however, 30%-40% became refractory to pharmacological therapies and could require surgical treatment. The causes of pharmacological refractoriness are poorly understood. Multidrug-resistance (MDR) mechanisms observed in cancer, could be also present in Refractory Epilepsy (RE). The ATP-binding-cassette (ABC) transporters may develop MDR phenotype preventing anti-epileptic drugs (AEDs) to reach their parenchyma brain targets. MDR-1 gene encoded P-glycoprotein (P-gp), is constitutively expressed in excretory tissues, including vascular endothelial cells (VEC) of the blood-brain-barrier. Here, we describe several MDR proteins over-expressed in VEC, astrocytes and neurons from adults and pediatric RE patients. Surgically treated cases showed brain P-gp over-expression with persistent plasmatic low levels of AEDs, and/or accelerated 99mTc-MIBI hepatic clearance. Experimentally, we oberved taht a sequential and progressive seizure-induced P-gp over-expression fromVEC-astrocytes- neurons correlates with increasing refractoriness to phenytoin treatment. Clinically and esxperimentally , we oberved that nimodipine reverts RE phenotype. Because P-gp depolarizes potential membrane of P-gp-expressing tumor-cells, we hypothesized that weaker glutamic stimulation may totally depolarizes to P-gp-expressing neurons, inducing persistent low convulsive-threshold and playing a role in epileptogenesis mechanisms Pharmacological control of ABC-transporters could avoid the current invasive surgical treatments for Refractory Epilepsy.