Endothelial brain endothelium

The main component of the blood-brain barrier is the brain endothelium, which exhibits a physical, an efflux and a metabolic barrier for the transport of drugs into the CNS. The physical barrier, an efflux, is a result of the tight junctions between adjacent endothelial cells, which are around 50-100 times tighter than in the peripheral endothelium, so that penetration across the endothelium is effectively confined to transcellular mechanisms [26, 27]. These junctions significantly restrict even the movement of small ions such as Na" " and Cl , so that the transendothelial electrical resistance (TEER), which is typically 2-20 2 cm in peripheral capillaries, can be over 1000 1 cm in brain endothelium [28]. 

Capillaries in the Brain (the Blood-Brain Barrier). Capillaries in the brain are less permeable than capillaries in other tissues. This limited permeability, which is frequently called the blood-brain barrier, is essential for brain function. Reduced permeation provides a buffer that maintains a constant brain extracellular environment, even at times when blood chemistry is changing. The basis for this lower permeability is the relative paucity of pores in the brain endothelium. Therefore, molecules that move from blood to brain must diffuse through the endothelial cell membranes. As expected from this observation, the permeability of brain capillaries depends on the size and lipid solubility of the solute. In general, molecules that are larger than several hundred in molecular weight do not permeate into the brain. Empirical relationships between cerebrovascular permeability and the oil / water partition coefficient have been developed [26] (see Figure 5.27) ... 

The blood-brain barrier forms the interface between the bloodstream and the brain parenchyma and thus controls the passage of endogenous substances and xenobiotics into and out of the central nervous system. Brain microvessels exhibit a variety of unique structural features, such as an extremely tight endothelium without fenestration, a very low rate of pinocytosis, tight junctions between endothelial cells excluding paracellular permeability, and a series of polarized transport proteins. The following chapter describes the structural and functional characteristics of the blood-brain barrier with emphasis on transport proteins, as well as in vitro techniques, which allow studying this complex barrier in the brain. 

The rat brain and macrophage NOS isoforms are soluble, dimeric enzymes, each comprised of two identical subunits (Stuehr et al., 1991a Schmidt et al., 1991). Denatured molecular weights for the various NOS isoforms range from 130 to 150 kDa. The endothelium NOS is of unknown quaternary composition, and localizes primarily in the membrane fraction (Pollock et al., 1991), due to posttranslational myristoylation near the N-terminus (Lamas etaL, 1992). Phosphorylation consensus motifs are present on the brain and endothelial isoforms, with phosphorylation possibly down regulating NOS activity or preventing localization onto the membrane (Bredt et al., 1992 Michel et al., 1993). 

Added to these two layers is an additonal barrier formed by the brain itself. Foot-like projections of brain cells called astrocytes encase the collagenous basement membrane forming a glial sheath. These cells are believed to "induce" the formation of the tight junction of the endothelium. In addition the endothelial blood cells and astrocytes contain enzymes which can alter an invading... 

Protection of vascular endothelial cells from oxygen free radical damages Enhancement of SOD, catalase and peroxidase in the cytosol of kidney Protection of pulmonary endothelium against free radicals in rabbits Protection of lipid peroxidation in liver and cardiac muscle in rats Inhibition of lipid peroxidation of rat liver and brain microsomes Inhibition of lipid peroxidation in serum and liver in rats Protective effect of ginsenosides on reperfusion injuries... 

Preston et al. [66] have shown that BBB permeability to the nonmetabolizable, but slowly BBB penetrant, tracer mannitol (182 Da), is between 0.19 and 0.22 pL/g/min in the brain of rats of 1 week of age and this permeability is identical to that of adult rats. The vascular space occupied by the tracer mannitol (the initial volume of distribution Fj) falls from 1.23 mL, at 1 week of age, to 0.75 mL per 100 g brain in the adult rat [66], indicating either a larger vascular volume, resulting from a greater capillary density or capillary diameter in the neonatal rat, or to a significant degree of internalization of the mannitol by the endothelium, possibly by fluid-phase endocytosis into the cerebral capillary endothelial cells in the newborn, compared to the adult. 

The distribution of drugs depends on both the physicochemical properties of the drug molecules and the composition of tissue membranes. These factors can either result in a uniform or uneven distribution of dmgs into the various body compartments and fluids. In the extreme, distribution may tend toward an accumulation of drugs in particular tissues or to an almost complete exclusion of the drag from a particular compartment in a defined length of time. One unique compartment that has to be considered in this respect is the brain, which is separated from the capillary system of the blood by the blood-brain barrier, whose membrane has a special structure. It consists of a cerebral capillary network formed by a capillary endothelium that consists of a cell layer with continuous compact intercellular junctions. It has no pores, but special cells, astrocytes, which support the stability of the tissues, are situated at the bases of the endothelial membrane separating the brain and CSF from the blood. The astrocytes form an envelope around the capillaries. 

The brain capillary endothelium comprises the lumenal and ablumenal membranes of capillaries, which are separated by approximately 300 ran of endothelial cytoplasm (Figure 13.2). The structural differences between brain capillary endothelium and non-brain capillary endothelium are associated with the endothelial tight junctions. The non-brain capillaries have fenestrations (openings) between the endothelial cells through which solutes can move readily via passive diffusion. In brain capillaries, the endothelium has epithelial-like tight junctions which preclude movement via paracellular diffusion pathways. There is also minimal pinocytosis across brain capillary endothelim, which further limits transport of moieties from blood to brain. 

In addition to the endothelial cells, the cerebral micro-vasculature (Figure 13.3) also contains pericytes (phagocytic cells) located on the brain side of the endothelium, which share a common basement membrane with the endothelial cell. There are about 3 endothelial cells for every pericyte. They probably play an important role in drag passage across the BBB, but have not been studied very extensively. In the brain,... 

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