Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders

Abstract

The strength of the blood-brain barrier (BBB) in providing protection to the central nervous system from exposure to circulating chemicals is maintained by tight junctions between endothelial cells and by a broad range of transporter proteins that regulate exchange between CNS and blood. The most important transporters that restrict the permeability of large number of toxins as well as therapeutic agents are the ABC transporters. Among them, P-gp, BCRP, MRP1 and MRP2 are the utmost studied. These efflux transporters are neuroprotective, limiting the brain entry of neurotoxins; however, they could also restrict the entry of many therapeutics and contribute to CNS pharmacoresistance. Characterization of several regulatory pathways that govern expression and activity of ABC efflux transporters in the endothelium of brain capillaries have led to an emerging consensus that these processes are complex and contain several cellular and molecular elements. Alterations in ABC efflux transporters expression and/or activity occur in several neurological diseases. Here, we review the signaling pathways that regulate expression and transport activity of P-gp, BCRP, MRP1 and MRP2 as well as how their expression/activity changes in neurological diseases.

Perspectives on Dual Targeting Delivery Systems for Brain Tumors

“…Additionally, efflux transporters, such as p-glycoprotein, multiple drug resistance protein 4 and breast cancer cell resistance protein, are present on the BBB. They pump drugs out of the brain which further attenuates drug concentrations (Qosa et al 2015). As a result, only about 98 % of small molecules and nearly all of free peptides, proteins and genes cannot directly penetrate through the BBB (Pardridge 2007).…”

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

“…This inhibition of PGE 2 production will reducethe proinflammatory lipid signaling pathway in HCC cells, which has been suggested to down-regulateABC transporters in cancer cells. 12,14–16 …”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…Bár a betegség oka ismeretlen, igazolták a környezeti neurotoxinok fokozott jelenlétének rizikónövelő hatását. A vér-agy gát detoxikáló hatásának csökkenésében az ott lokalizálódó pumpafehérjék csökkent expressziója, illetve aktivitása áll [62][63][64]. Az MDR1 gén genetikai polimorfizmusát is a Parkinson-kór rizikófaktorai közé sorolják [65,66].…”

“…AIDS-es betegek agyi szövetmintái-ban a gliasejteken fokozott P-gp-, a vér-agy gátban fokozott MRP1-expressziót találtak [69,70]. Ez az eredmény összefüggést mutat azzal, hogy a vírus a citokinek kiválasztását fokozza, amely szintén növeli a transzporterfehérje-expressziót az agyi kapilláris endothelsejteken és az astrocytákon [62,71]. Ugyanakkor kimutatták, hogy két HIV-ellenes gyógyszer: az atazanavir és a ritonavir növeli a P-gp-expressziót in vitro sejtvonalon és primer human endothelsejt-kultúrán [72,73].…”