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2000
Volume 1, Issue 3
  • ISSN: 1574-8855
  • E-ISSN: 2212-3903

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 observed that a sequential and progressive seizures-induced P-gp over-expression from VEC → astrocytes → neurons correlated with increasing refractoriness to phenytoin treatment. Clinically and experimentally, we observed 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.

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/content/journals/cdth/10.2174/157488506778194910
2006-09-01
2025-06-15
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/content/journals/cdth/10.2174/157488506778194910
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  • Article Type:
    Research Article
Keyword(s): 99mTc-MIBI; AEDs; BCRP; Multidrug resistance epilepsy
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