Efflux proteins at the blood–brain barrier: review and bioinformatics analysis

Abstract

1. Efflux proteins at the blood-brain barrier provide a mechanism for export of waste products of normal metabolism from the brain and help to maintain brain homeostasis. They also prevent entry into the brain of a wide range of potentially harmful compounds such as drugs and xenobiotics. 2. Conversely, efflux proteins also hinder delivery of therapeutic drugs to the brain and central nervous system used to treat brain tumours and neurological disorders. For bypassing efflux proteins, a comprehensive understanding of their structures, functions and molecular mechanisms is necessary, along with new strategies and technologies for delivery of drugs across the blood-brain barrier. 3. We review efflux proteins at the blood-brain barrier, classified as either ATP-binding cassette (ABC) transporters (P-gp, BCRP, MRPs) or solute carrier (SLC) transporters (OATP1A2, OATP1A4, OATP1C1, OATP2B1, OAT3, EAATs, PMAT/hENT4 and MATE1). 4. This includes information about substrate and inhibitor specificity, structural organisation and mechanism, membrane localisation, regulation of expression and activity, effects of diseases and conditions and the principal technique used for in vivo analysis of efflux protein activity: positron emission tomography (PET). 5. We also performed analyses of evolutionary relationships, membrane topologies and amino acid compositions of the proteins, and linked these to structure and function.

Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

“…In an open treatment study which used amisulpride use in older people with AD psychosis and very late-onset (>60 years) schizophrenia-like psychosis (VLOSLP), treatment response and parkinsonism occurred at very low doses (25-75mg/day AD, 50-100mg/day VLOSLP), and at correspondingly low blood drug concentrations (40-100ng/ml AD, 40-169ng/ml VLOSLP) due to higher than anticipated striatal dopamine D2/3 receptor occupancies (caudate occupancy, steady state treatment, 50mg/day amisulpride; 41-83% AD, 41-59% VLOSLP) (Clark-Papasavas et al 2014)(Reeves et al 2016)(Reeves et al 2017)(Clark-Papasavas et al 2014)(Reeves et al 2018). These findings strongly implicate age and AD-specific changes in central pharmacokinetics in antipsychotic drug sensitivity, particularly at the BBB, which controls drug entry through the expression of transporters (Saidijam et al 2017). Furthermore, they suggest that amisulpride (Dos Santos Pereira et al 2014)(Natesan et al 2008) is a sufficiently sensitive tool with which to probe BBB functionality.…”

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

“…The central nervous system (CNS), and other body compartments like the gonads [ 238 , 239 ], maintain a barrier that tightly regulates accessibility of hydrophilic nucleoside analogues [ 240 , 241 , 242 , 243 , 244 , 245 ]. The efficacy of the blood-brain barrier (BBB) to shield the CNS from antimetabolites is historically best documented by children with ALL who–despite achieving complete remission when treated with antifolates [ 4 ]—almost universally relapsed with CNS disease.…”

“…hCNTs, with the exception of hCNT3 [ 279 ], are expressed in a tissue-restricted manner, mainly in intestinal and renal epithelia, and transport nucleosides in a monodirectional sodium- or hydrogen-dependent manner with specificity for pyrimidines (hCNT1), purines (hCNT2), or both (hCNT3). hENT1-3 are ubiquitously expressed, and hENT4 is mainly present in brain and heart [ 243 , 277 , 280 ]. Whereas nucleobases like thiopurines and 5-FU can only be transported by hENTs, nucleoside analogues can be transported both by hENTs and hCNTs (an overview of transporter affinity for individual nucleoside analogues can be found here: [ 278 ]).…”

Cell Migration Related to MDR—Another Impediment to Effective Chemotherapy?

“…One of the most important functions of ABC proteins as efflux pumps is the creation of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB), which maintain brain homeostasis by eliminating metabolic waste products and preventing the uptake of both endogenous and exogenous potentially harmful substances [ 105 , 106 , 107 ]. The BBB is composed of a monolayer of brain microvessel endothelial cells joined by tight junctions to create an impermeable barrier surrounded by pericytes, astrocytes, and neurons.…”