Biomedical Engineering Reference
In-Depth Information
endothelial cells. Pericytes provide microvasculature structural support and
vasodynamic capacity.
BCSFB function, together with the BBB and the meninges, is the con-
trol of the brain internal environment. It is sited at the choroid plexus epi-
thelium, secreting CSF, which circulates through the ventricles and around
the outside of the brain and spinal cord [14]. The choroidal epithelium is
a complex organ with many additional functions including neuroendocrine
signaling, neuroimmune and neuroinflammatory responses, drug and toxin
metabolism, and transport. On the external surface of the brain the ependy-
mal cells fold over upon themselves to form a double layered structure. This
virtual space is known as “subarachnoid space” and acts in CSF drainage.
The passage of substances from the blood through the arachnoid membrane
is prevented by tight junctions. The capillary endothelium in the choroid
plexus is fenestrated, allowing the passage of small molecules. The arach-
noid membrane is generally impermeable to hydrophilic substances and its
role in the formation of the blood-CSF barrier is largely passive.
TJs are located on the apical region of endothelial cells and are structur-
ally formed by a complex network made of a series of parallel, intercon-
nected, transmembrane and cytoplasmatic strands of proteins [15]. TJs
consist of three integral membrane proteins, namely, claudin, occludin, and
junction adhesion molecules, and a number of cytoplasmic accessory pro-
teins including ZO-1, ZO-2, ZO-3, cingulin. The high level of integrity of
TJs is reflected by the high electrical resistance of the BBB (1500-2000 Ω
cm
2
), which depends on a proper extracellular Ca2+ ion concentration. The
tightness of the BBB is due to the physical complexity of its junctional struc-
ture and the molecular substructure, in particular, the presence of trans-
membrane proteins claudins 1 and 5 which help to seal the intercellular cleft.
Cytoplasmic proteins link membrane proteins to actin, which is the primary
cytoskeleton protein for the maintenance of structural and functional integ-
rity of the endothelium. In a recent study, treatment of claudin-5 by cyclic
AMP (cAMP) led to enhancement of claudin-5 activity along cell borders,
rapid reduction in transendothelial electrical resistance (TER), and loosen-
ing of the claudin-5-based endothelial barrier against mannitol [16]. These
suggest that manipulation of claudin-5, or potentially other TJ proteins may
permit drug transport by altering the function at the BBB but without its
total disruption. Occludin is a phosphoprotein with four transmembrane
domains. Occludin appears to be a regulatory protein that can alter para-
cellular permeability. Occludins and claudins assemble into heteropolymers
and form intramembranous strands.
Adherens junctions (AJs) are located below the TJs in the basal region of
the lateral plasma membrane. They are composed of trans-membrane gly-
coproteins (cadherins) linked to the cytoskeleton by cytoplasmatic proteins,
thus providing an additional tightening structure between the adjacent en-
dothelial cells at the BBB. The cytoplasmic domains of cadherins bind to the
