Physiology of Blood–Brain
Interfaces in Relation to Brain Disposition of Small Compounds and
Macromolecules
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Abstract
The brain develops and functions within a strictly controlled
environment resulting from the coordinated action of different cellular
interfaces located between the blood and the extracellular fluids
of the brain, which include the interstitial fluid and the cerebrospinal
fluid (CSF). As a correlate, the delivery of pharmacologically active
molecules and especially macromolecules to the brain is challenged
by the barrier properties of these interfaces. Blood–brain
interfaces comprise both the blood–brain barrier located at
the endothelium of the brain microvessels and the blood–CSF
barrier located at the epithelium of the choroid plexuses. Although
both barriers develop extensive surface areas of exchange between
the blood and the neuropil or the CSF, the molecular fluxes across
these interfaces are tightly regulated. Cerebral microvessels acquire
a barrier phenotype early during cerebral vasculogenesis under the
influence of the Wnt/β-catenin pathway, and of recruited pericytes.
Later in development, astrocytes also play a role in blood–brain
barrier maintenance. The tight choroid plexus epithelium develops
very early during embryogenesis. It is specified by various signaling
molecules from the embryonic dorsal midline, such as bone morphogenic
proteins, and grows under the influence of Sonic hedgehog protein.
Tight junctions at each barrier comprise a distinctive set of claudins
from the pore-forming and tightening categories that determine their
respective paracellular barrier characteristics. Vesicular traffic
is limited in the cerebral endothelium and abundant in the choroidal
epithelium, yet without evidence of active fluid phase transcytosis.
Inorganic ion transport is highly regulated across the barriers. Small
organic compounds such as nutrients, micronutrients and hormones are
transported into the brain by specific solute carriers. Other bioactive
metabolites, lipophilic toxic xenobiotics or pharmacological agents
are restrained from accumulating in the brain by several ATP-binding
cassette efflux transporters, multispecific solute carriers, and detoxifying
enzymes. These various molecular effectors differently distribute
between the two barriers. Receptor-mediated endocytotic and transcytotic
mechanisms are active in the barriers. They enable brain penetration
of selected polypeptides and proteins, or inversely macromolecule
efflux as it is the case for immnoglobulins G. An additional mechanism
specific to the BCSFB mediates the transport of selected plasma proteins
from blood into CSF in the developing brain. All these mechanisms
could be explored and manipulated to improve macromolecule delivery
to the brain