Key Points
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The value of many promising drug candidates is diminished by the presence of barriers between blood and brain that possess both structural and enzymatic components at the level of the cerebral capillaries, the epithelia of the choroid plexuses and other circumventricular organs, and the arachnoid membranes.
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Cerebral capillaries comprise approximately 95% of the total area of the barriers between blood and brain. They are the main entry route for molecules into the CNS as well as the major hurdle that impedes most neuropharmaceuticals from eliciting a desired pharmacological effect at an obtainable dose.
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The blood–brain barrier (BBB) is implicated in pathologies such as neurodegenerative disorders, stroke and traumatic brain injury as well as in infectious processes and inflammatory pain. BBB dysfunction in these pathologies may result in compromised transport and permeability properties of the barrier as well as in alterations in cerebrovascular regulatory mechanisms of blood flow, with ensuing perturbed signalling between brain endothelium and associated cells, such as glia and neurons.
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By modelling the BBB it is possible to make predictions about brain uptake of potential drug candidates and to study the effect of therapeutic interventions at the level of the cerebral capillaries. This provides not only powerful means to assess the risk for taking compounds further in the pharmaceutical development process, but also generates important information to allow for rational drug design.
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To optimize drug design and develop therapies targeted at disease mechanisms involving the BBB or to improve drug delivery to the CNS, BBB models are required that adequately reflect in vivo conditions.
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A shift from small molecules towards biopharmaceuticals in major pharmaceutical companies is likely to lead to increased efforts in developing and evaluating strategies to improve the delivery of large molecules to the brain. An integrative use of in vitro BBB models and in vivo techniques, together with advances in medicinal chemistry and tailor-made design of antibodies, proteins and peptides, are likely to be of key importance.
Abstract
The market for neuropharmaceuticals is potentially one of the largest sectors of the global pharmaceutical market owing to the increase in average life expectancy and the fact that many neurological disorders have been largely refractory to pharmacotherapy. The brain is a delicate organ that can efficiently protect itself from harmful compounds and precisely regulate its microenvironment. Unfortunately, the same mechanisms can also prove to be formidable hurdles in drug development. An improved understanding of the regulatory interfaces that exist between blood and brain may provide novel and more effective strategies to treat neurological disorders.
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This work was supported by grants from the Ministry of Research of France (fellowship to M. Culot).
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Glossary
- Choroid plexus
-
Site of cerebrospinal fluid production in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.
- Circumventricular organs
-
Small structures bordering the ventricular spaces in the midline of the brain that have common morphologic and endocrine-like characteristics. They make cellular contacts with both blood and cerebrospinal fluid.
- Arachnoid membrane
-
A fibrous membrane that covers the brain and spinal cord. It is separated from the pia mater by the subarachnoid space in which the cerebrospinal fluid flows.
- Astrocytic end-feet
-
Part of the astrocyte which envelopes the capillary endothelium in the brain.
- Pericyte
-
A cell of mesodermal origin and contractile-phagocytic phenotype that is associated with the outer surface of brain capillaries. It is embedded in the basal lamina between astrocyte end-feet and endothelium.
- Transcytosis
-
An energy-requiring mode of transport across cells that involves vesicles endocytosing from one membrane (for example, blood side) and releasing contents at the opposite side (for example, brain side).
- Transendothelial electrical resistance
-
In this Review, this refers to the electrical resistance across the BBB. The high electrical resistance of the mature BBB is considered to be due to its complex tight junctions.
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Cecchelli, R., Berezowski, V., Lundquist, S. et al. Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Discov 6, 650–661 (2007). https://doi.org/10.1038/nrd2368
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DOI: https://doi.org/10.1038/nrd2368
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