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FIGURE 16.1 Three-dimensional artist's rendition of the BBB. The CNS capillary endothelial cells, with their abundant mitochondria and tight junctions (shown in yellow), constitute the structural basis for the blood-brain barrier. The capillary endothelium is 95 per cent covered by glial foot processes (red), and surrounded by the basal lamina, pericytes (orange), and perivascular phagocytes (blue). See Plate 16.1 in Color Plate Section.

FIGURE 16.1 Three-dimensional artist's rendition of the BBB. The CNS capillary endothelial cells, with their abundant mitochondria and tight junctions (shown in yellow), constitute the structural basis for the blood-brain barrier. The capillary endothelium is 95 per cent covered by glial foot processes (red), and surrounded by the basal lamina, pericytes (orange), and perivascular phagocytes (blue). See Plate 16.1 in Color Plate Section.

the transmembrane tight junction proteins to the cytoskeleton. Adherens junctions are necessary for the primary contact between endothelial cells and formation of tight junctions. The cadherin-catenin system of adherens junction is also important for established tight junction morphology and function. Signaling pathways involved in tight junction regulation involve G-proteins, serine-, threonine-, and tyrosine kinases, calcium, cAMP, proteases and cytokines [12,13].

The BBB is absent at the pituitary and pineal glands, median eminence, area postrema, subfornical organ and lamina terminalis [2,14,15]. In these areas (the so-called ''circumventricular organs''), the capillary endothelial cells are fenestrated, permitting molecules to pass more freely [1,14]. Substances which do not readily cross the BBB may reach the CNS by means of entry at these more vulnerable sites [8]. Another type of cell, the tanycyte, is found associated with the circumventricular organs, as well as in the region of the third ventricle, cerebral aqueduct, floor of the fourth ventricle, and in the cervical spinal canal [3]. Tanycytes are somewhat like ependymal cells, but have few cilia. They may play a role in the transport of biogenic amines, which initiate the secretion of pituitary hormone release factors [16]. Recent evidence has also indicated that tanycytes may have a CNS regenerative function [17].

The blood-CSF barrier is the other major interface between the circulatory system and the CNS. By way of comparison however, the surface area available for exchange at the blood-CSF barrier is 1/5000th that of the BBB [18]. The blood-CSF barrier exists at the choroid plexus and in the subarachnoid space. The underlying vasculature of the choroid plexus consists of fenestrated, thin-walled, relatively large-diameter capillaries [3]. The epithelial cells of the choroid plexus, which constitute the blood-CSF barrier, have apical tight junctions only [1,8,13]. Fixed macrophages are associated with the choroid plexus. These cells are sometimes referred to as Kolmer or epiplexus cells. While most CSF is secreted by the choroid plexus, some is also produced by brain capillaries. The CSF flows through the ventricles of the brain, and a series of cisterns and subarachnoid spaces outside the brain and spinal cord, then is absorbed by bulk flow into the venous system at the arachnoid villi (or pacchionian granulations). The ependyma—which resembles renal tubular epithelium—constitutes the brain-CSF barrier [8].

While the ventricles are lined with the ependymal cells, the cisterns and spaces outside the brain are lined with arachnoid and pial cells [3]. Blood vessels run along the outer surface of the CSF-containing subarachnoid space [3]. It had been thought that the pia mater follows the arteries and arterioles for some short distance as they descend into the brain parenchyma. The perivascular space between the descending vessel and the pia, often referred to as the Virchow-Robin space, was thought to communicate with the subarachnoid space. Scanning electron microscopy, however, has revealed that the pia actually surrounds a vessel as it travels through the subarachnoid space, but does not accompany the vessel as it descends into the brain parenchyma. Instead, the pia surrounding the vessel spreads out over the pia which is covering the surface of the brain, effectively excluding the perivascular space from the subarachnoid space [3]. Thus, Virchow-Robin spaces actually communicate with the brain extracellular fluid space (ECF), rather than the subarachnoid space. Small solutes diffuse freely between the ECF and the CSF.

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