ABC transporters in drug-resistant epilepsy: mechanisms of upregulation and therapeutic approaches. (June 2019)

• Record Type: Journal Article
• Authors: Leandro, Kevin; Bicker, Joana; Alves, Gilberto; Falcão, Amílcar; Fortuna, Ana
• Is Part Of: Pharmacological research. Volume 144(2019)
• Page Start: 357
• Page End: 376
• Publication Date: 2019-06
• Subjects: ABC ATP binding cassette -- AED antiepileptic drug -- BBB blood-brain barrier -- BCSFB blood cerebral spinal fluid barrier -- BSP bromosulfophthalein -- CETA concentration equilibrium transport assay -- CNS central nervous system -- COX-2 cyclooxygenase type 2 -- CYP cytochrome P450 -- DRE drug-resistant epilepsy -- DS Dravet syndrome -- EP1 prostaglandin E2 receptor 1 -- FCD focal cortical dysplasia -- [[18F]MPPF] [18F]-(2′-methoxyphenyl-(N-2′-pyridinyl)-p-fluoro-benzamido-ethyipiperazine) -- GLUT1 glucose transporter 1 -- HPLC high-performance liquid chromatography -- HS hippocampal sclerosis -- ILAE International League Against Epilepsy -- LC-MS Liquid chromatography–mass spectrometry -- MAM methylazoxymethanol acetate -- MCD malformations of cortical development -- MDCKII Madin-Darby canine kidney type II -- 3-MP 3-mercaptopropionic acid -- miRNA microRNA -- mRNA messenger ribonucleic acid -- NBD nucleotide-binding domain -- NF-κB Nuclear factor kappa B -- NMDA N-methyl-D-aspartate -- PET positron emission tomography -- PET/MRI positron emission tomography and magnetic resonance imaging -- PLGA poly-lactic-co-glycolic acid -- PXR pregnane X receptor -- RNAi RNA interference -- RT-PCR reverse transcription polymerase chain reaction -- SE status epilepticus -- shRNA short hairpin RNA -- siRNA small interfering RNA -- SLC solute carrier -- SNP single nucleotide polymorphism -- SXR steroid and xenobiotic receptor -- TLE temporal lobe epilepsy -- TMD transmembrane domain -- UV ultraviolet -- WHO World Health Organization; P-glycoprotein -- Multidrug resistance-associated proteins -- Breast cancer resistance protein -- Overexpression -- Efflux transporter; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.04.031
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Drug-resistant epilepsy (DRE) affects approximately one third of epileptic patients. Among various theories that try to explain multidrug resistance, the transporter hypothesis is the most extensively studied. Accordingly, the overexpression of efflux transporters in the blood-brain barrier (BBB), mainly from the ATP binding cassette (ABC) superfamily, may be responsible for hampering the access of antiepileptic drugs into the brain. P-glycoprotein and other efflux transporters are known to be upregulated in endothelial cells, astrocytes and neurons of the neurovascular unit, a functional barrier critically involved in the brain penetration of drugs. Inflammation and oxidative stress involved in the pathophysiology of epilepsy together with uncontrolled recurrent seizures, drug-associated induction and genetic polymorphisms are among the possible causes of ABC transporters overexpression in DRE. The aforementioned pathological mechanisms will be herein discussed together with the multiple strategies to overcome the activity of efflux transporters in the BBB – from direct transporters inhibition to down-regulation of gene expression resorting to RNA interference (RNAi), or by targeting key modulators of inflammation and seizure-mediated signalling.