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Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders.
- Source :
-
Pharmacology & therapeutics [Pharmacol Ther] 2020 Sep; Vol. 213, pp. 107554. Date of Electronic Publication: 2020 Apr 19. - Publication Year :
- 2020
-
Abstract
- ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.<br />Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Brain metabolism
Central Nervous System Agents pharmacokinetics
Central Nervous System Agents pharmacology
Drug Resistance
Humans
Nervous System Diseases drug therapy
ATP-Binding Cassette Transporters metabolism
Blood-Brain Barrier metabolism
Nervous System Diseases physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-016X
- Volume :
- 213
- Database :
- MEDLINE
- Journal :
- Pharmacology & therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 32320731
- Full Text :
- https://doi.org/10.1016/j.pharmthera.2020.107554