Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 437–449

Blood–brain barrier structure and function and the challenges for CNS drug delivery

Review

DOI: 10.1007/s10545-013-9608-0

Cite this article as:
Abbott, N.J. J Inherit Metab Dis (2013) 36: 437. doi:10.1007/s10545-013-9608-0

Abstract

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood–brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the ‘neurovascular unit’ (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.

Abbreviations

AAV

adeno-associated virus

ABC

ATP-binding cassette

ABCG2

BCRP

ADME

absorption, distribution, metabolism, excretion

AMT

adsorptive-mediated transcytosis

BBB

blood–brain barrier

BBEC

bovine brain endothelial cells (primary)

BCRP

breast cancer resistance protein

bEND3

mouse immortalised brain endothelial cell line

CNS

central nervous system

CSF

cerebrospinal fluid

CYP

cytochrome P450 enzyme

CVO

circumventricular organ

ERT

enzyme replacement therapy

GAGs

glycosaminoglycans

GLUT1

glucose carrier

hCMEC/D3

human immortalised brain endothelial cell line

hPSCs

human pluripotent stem cells

IL-1, IL17A

interleukins

INCL

infantile neuronal ceroid lipofuscinosis

IV

intravenous

Kp,uu

unbound drug brain:plasma concentration ratio

LAT1

large neutral amino acid carrier

LDL

low density lipoprotein

LogBB (or Kp)

total drug brain:plasma concentration ratio

LogDoctanol

log compound distribution coefficient octanol/buffer at given pH

LogPoctanol

log compound partition coefficient octanol/water, neutral species

LSD

lysosomal storage disease

MPR

mannose-6-phosphate receptor

MDR1 (or PgP)

P-glycoprotein

MMP

matrix metalloproteinase

MPS

mucopolysaccharidosis

MPSIIIA or B

Sanfilippo syndrome type A or B

MPSVII

Gaucher’s disease

miRNA

microRNA

NVU

neurovascular unit

PAMPA

parallel artificial membrane permeability assay

Papp

apparent permeability

PBEC

porcine brain endothelial cells (primary)

PBEC/As

PBEC co-cultured with rat astrocytes

PDGF-B

platelet-derived growth factor B

Pe

endothelial permeability

PgP

P-glycoprotein (or MDR1, ABCB1)

PS

permeability x surface area product

QSAR

quantitative structure-activity relationship

RBEC

rat brain endothelial cells (primary)

RBEC/As

RBEC co-cultured with rat astrocytes

RMT

receptor-mediated transcytosis

SAR

structure-activity relationship

SLC

small solute carrier

SRT

substrate-replacement therapy

TEER

transendothelial electrical resistance

XMET

xenobiotic metabolising enzymes and transporters

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.BBB Group, Institute of Pharmaceutical ScienceKing’s College LondonLondonUK