electrical resistance (>1,000-3,000 fi/cm). This structure prevents paracellular transport across the brain endothelium. These endothelial cells are separated from the astrocyte foot processes and pericytes by a basement membrane (Fig. 1). The astrocyte foot process are about 20 nm from the abluminal (the layer of plasma membrane of polarized cells that is adjacent to the basement membrane, also called basolateral membrane) surface of the endothelial cells and this space is mainly filled with the microvascular basement membrane and the brain extracellular fluid. The endothelial cells actively regulate vascular tone, blood flow, and barrier function in the brain microvasculature. Endothelial cells are thin, about 0.1 mm thick, and thus occupy about 0.2% of the volume of the whole brain. They are polarized, like epithelial cells; the luminal (the layer of plasma membrane on the side toward the lumen of polarized cells, also called apical membrane) and abluminal endothelial membranes each segregate specific transcellular transport across the brain endothelium (Zlokovic 2008). This cell polarity is well illustrated by the distribution of several enzymes. Alkaline phosphatase is equally distributed between the luminal and the abluminal membranes but Na, K-ATPase and 5'-nucleotidase are present primarily on the abluminal side, and gamma-glutamyl transpeptidase is found mainly on the luminal side. Goldmann first postulated that the brain capillaries provide the anatomical basis of a barrier in 1913, but this was not conclusively demonstrated until the 1960s, when electron microscope studies revealed that the endothelial cells of a brain capillary form electron-dense junctional contact between two adjacent cells. There are no gap junctions (specialized intercellular connections
Blood-Brain Barrier. Fig. 1. Anatomical and functional definition of the blood-brain barrier (BBB). The cross-sectional scheme shows that the brain capillary endothelial cell is sealed by tight junctions which are surrounded by the pericyte and astrocyte foot processes. All these cellular components are separated by a basal membrane and constitute the neurovascular unit. Solutes can cross the cerebral endothelial cells by passive diffusion or active transport involving influx and efflux transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies. Enzymes can also metabolize solutes.
between cells allowing solute exchanges between adjacent cells) in brain capillaries and postcapillary venules and the tight junctions are responsible for sealing adjacent cells and maintaining cell polarity. Tight junctions are membrane microdomains made up of many specific proteins engaged in a complex membranar and intracytosolic network. Continuous tight junctions are not the only feature that makes the blood vessels of the brain different from those of other tissues. There are no detectable fenestra-tions or single channels between the blood and interstitial spaces. They contain fewer pinocytotic vesicles (cytoplas-mic vesicles resulting from a mechanism by which extracellular fluid is taken into a cell following the invagination of the cell membrane) than do endothelial cells in the peripheral microvasculature and there is evidence that the majority of what appear to be independent vesicles in the endothelium cytoplasm are part of membrane invaginations that communicate with either the blood or the perivascular space. The endothelial cells that form the BBB also contain many mitochondria. They occupy 8-11% of the cytoplasmic volume, much more than in brain regions lacking a BBB and tissues outside the CNS. This indicates that the BBB also functions as a metabolic barrier, in addition to its physical barrier properties (Ballabh et al. 2004). There are highly specific transport systems carrying nutrients at the luminal or abluminal sides, or at both sides of the endothelial cell membrane. These carrier-mediated transport systems regulate the movement of nutrients between the blood and the brain. The brain capillary endothe-lium also bears specific receptors for circulating peptides or plasma proteins and these mediate the ► transcytosis of peptides or proteins through the BBB. More recently, the discovery of active carrier-mediated transporters which are not involved in transporting substrate from the blood to the brain, but from the brain to the blood, has greatly reinforced the barrier properties of the BBB. Most of these transmembrane proteins are located at the lumi-nal or abluminal membranes of the endothelial cells and restrict the uptake of numerous drugs by the brain. Thus a large number of amphipathic cationic drugs are efflu-xed by one ATP-binding cassette (ABC) protein, the ► P-glycoprotein (P-gp) which is present at the luminal surface of the BBB. Brain vessels also have more classical types of receptors, including a-and b-adrenergic receptors and receptors for serotonin, adenosine, histamine, angio-tensin, and arginine vasopressin. The brain capillaries are also almost completely surrounded by other cells, like pericytes and the astrocyte foot processes. Pericytes lie periendothelially on the abluminal side of the microves-sels (Fig. 1). A layer of basement membrane separates the pericytes from the endothelial cells and the astrocyte foot processes. Pericytes send out cell processes which penetrate the basement membrane and cover around 20-30% of the microvascular circumference. Pericyte cytoplasmic projections encircling the endothelial cells provide both a vasodynamic capacity and structural support to the micro-vasculature. CNS pericytes can be viewed as housekeeping scavenger cells and a second line of defense in the BBB. The blood capillaries of the CNS of vertebrates are also enveloped by a perivascular sheath of glial cells, mainly astrocytes (Fig. 1). Immunohistochemical and morphometric studies on astrocytes and the microvasculature of the human cerebral cortex have shown that the astrocyte perivascular processes form a virtually continuous sheath around the vascular walls. While the astrocytes themselves do not form the barrier, they have an important role in the development and maintenance of the BBB. Astrocytes release factors that can induce the BBB phenotype and/ or the angiogenic transformation of brain endothelial cells in vitro and in vivo. All these cellular components of the brain capillaries are joined by junctional systems. Zonal and extensive tight junctions seal the endothelial cells and gap junctions connect the endothelium to the subjacent pericyte layer, allowing their functional coupling and also weld them to the astrocyte processes (Abbott et al. 2006). The last component of the neurovascular unit is the nerve fibers, which may be seen close to the cerebral blood vessels; these may be noradrenergic and peptidergic nerves (Fig. 1). They influence the cerebrovascular tone and blood flow by secreting classical transmitters and a number of peptides, including substance P and vasoactive intestinal peptide. This neurogenic influence could also explain the circadian variation in the permeability of the BBB under noradrenergic influence. The intimate relationships between these cells make the BBB a pluricellular interface between the blood and the brain extracellular fluid.
Role of the Neurovascular Unit in Psychopharmacology
This overview points out the complexity of the BBB, as at least four types of cells plus the basement membrane are implicated in its structure and function. Thus many genes and the proteins they encode play a critical role in the broad pharmacological spectrum of activities carried out by the BBB. As psychoactive drug responses depend on numerous proteins in the body, including metabolizing enzymes, transporters, receptors, and all signaling networks mediating the response, it is very likely that geneprotein-mediated events at the BBB can play a role in the efficacy and safety of psychopharmacotherapies. For example, polymorphisms in genes encoding drug-metabolizing enzymes or transporters expressed at the
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