Drug Transport in the Brain

Ashraf, Tamima; Ronaldson, Patrick T.; Bendayan, Reina

doi:10.1002/9781118705308.ch14

Cited by 5 publications

(24 citation statements)

References 257 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of p -glycoprotein (Pgp) has been considered in many studies [ 243 , 473 – 490 ] that indicate that it does play a role, but there have also been studies suggesting that it does not [ 491 – 494 ]. P -glycoprotein is present in the luminal membranes of the endothelial cells (see Sect.…”

Section: Clearance Of Specific Substancesmentioning

confidence: 99%

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Hladky

Barrand

2018

Fluids Barriers CNS

165

156

View full text Add to dashboard Cite

This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g−1 min−1). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood–brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CLperivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood–brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood–brain barrier, have higher total CL values. Substances crossing the blood–brain barrier may do so by passive, non-specific means with CLblood-brain barrier values ranging from < 0.01 for inulin to > 1000 for water and CO2. CLblood-brain barrier values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood–brain barrier producing CLblood-brain barrier values > 50. The principal route for movement of Na+ and Cl− ions across the blood–brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CLblood-brain barrier values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood–brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-β efflux, which is measurably faster than efflux of inulin, is primarily across the blood–brain barrier. Amyloid-β also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-β reaches arterial walls resulting in cerebral amyloid angiopathy.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0113-6) contains supplementary material, which is available to authorized users.

show abstract

Section: Clearance Of Specific Substancesmentioning

confidence: 99%

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Hladky

Barrand

2018

Fluids Barriers CNS

165

156

View full text Add to dashboard Cite

show abstract

“…The BBB is comprised of a monolayer of non-fenestrated brain microvessel endothelial cells surrounded by pericytes, astrocytes, and neurons (8). The brain microvessel endothelial cells are joined by tight junctions that form a continuous impermeable barrier that limits paracellular flux.…”

Section: Blood-brain Barriermentioning

confidence: 99%

SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers

Morris

Rodriguez-Cruz

Felmlee

2017

AAPS J

129

107

View full text Add to dashboard Cite

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) separate the brain and cerebrospinal fluid (CSF) from the systemic circulation and represent a barrier to the uptake of both endogenous compounds and xenobiotics into the brain. For compounds whose passive diffusion is limited due to their ionization or hydrophilicity, membrane transporters can facilitate their uptake across the BBB or BCSFB. Members of the solute carrier (SLC) and ATP-binding case (ABC) families are present on these barriers. Differences exist in the localization and expression of transport proteins between the BBB and BCSFB, resulting in functional differences in transport properties. This review focuses on the expression, membrane localization, and different isoforms present at each barrier. Diseases that affect the central nervous system including brain tumors, HIV, Alzheimer's disease, Parkinson's disease, and stroke affect the integrity and expression of transporters at the BBB and BCSFB and will be briefly reviewed.

show abstract

“…Maintenance of BBB properties also requires contribution from other CNS cellular constituents such as pericytes, astrocytes, microglia, and neurons, a concept known as the neurovascular unit (NVU). 12 Capillary endothelial cells lack fenestration, display abundant junctional complexes composed of tight and adherens junctions, and have limited pinocytosis. These factors greatly restrict paracellular and transcellular transport of circulating solutes.…”

Section: Introductionmentioning

confidence: 99%

“…Nonspecific transport processes (ie, adsorptive endocytosis) also exist at the BBB and involve electrostatic interactions where cationic proteins bind with anionic binding sites. 12,14–17 In contrast, drugs—effectively being solutes with specific kinetic and structural properties—may require putative membrane transporters to get into, and to get out of, brain microvascular endothelial cells. Drug transport mechanisms at the BBB involve numerous proteins of the solute carrier (SLC) and the adenosine triphosphate (ATP)-binding cassette (ABC) superfamilies (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Brzica

Abdullahi

Ibbotson

et al. 2017

J Cent Nerv Syst Dis

View full text Add to dashboard Cite

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

show abstract

Drug Transport in the Brain

Cited by 5 publications

References 257 publications

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Contact Info

Product

Resources

About