Cell movement across, blood-brain

Cell Movement Across the Blood-Brain Barrier.588... 

Cell Movement across the Blood-Brain Barrier... 

Brain vascular endothelial cells are linked by tight junction proteins creating high-resistance junctions between cells that effectively prevent the movement of hydrophilic substances, including electrolytes, such as Na and K+. Water moves across the lipid bilayer of endothelial cells through simple diffusion and vesicular transport (Tait et al., 2008). However, specialized water channels are formed by molecules called aquaporins (AQPs), which are highly expressed in blood-brain interfaces to facilitate the transport of water across cell membranes. 

Figure 3.2. Potential mechanisms for drug movement across the blood-brain barrier. Routes of passage include passive diffusion through the brain capillary endothelial cells (A) utilization of inwardly directed (i.e. towards brain) transport or carrier systems expressed on brain capillary endothelial cells (B) utilization of outwardly directed (i.e. towards blood) efflux transport systems (C) or inclusion in various endocytic vesicular transport processes occurring within the brain capillary endothelial cells (D).

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]. 

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. 

Transport of amino acids into cells is mediated by specific membrane-bound transport proteins, several of which have been identified in mammalian cells. They differ in their specificity for the types of amino acids transported and in whether the transport process is linked to the movement of Na+ across the plasma membrane. (Recall that the gradient created by the active transport of Na+ can move molecules across membrane. Na+-dependent amino acid transport is similar to that observed in the glucose transport process illustrated in Figure 11.28.) For example, several Na+-dependent transport systems have been identified within the lumenal plasma membrane of enterocytes. Na+-independent transport systems are responsible for transporting amino acids across the portion of enterocyte plasma membrane in contact with blood vessels. The y-glutamyl cycle (Section 14.3) is believed to assist in transporting some amino acids into specific tissues (i.e., brain, intestine, and kidney). 

Factors Regulating Movement. The body requires water. To ensure that this requirement is fulfilled, the sensation of thirst creates a conscious desire for water. The sensation of thirst is caused by nerve centers in the hypothalamus of the brain which monitors the concentration primarily of sodium In the blood. When the sodium concentration, and hence the osmolarity of the blood, increases above the normal 310 to 340 mg/100 ml (136 to 145 mEq/liter), cells in the thirst center shrink. They shrink because the increased osmotic pressure of the blood pulls water out of their cytoplasm. This shrinking causes more nervous impulses to be generated in the thirst center, thus creating the sensation of thirst. Increased osmolarity of the blood is primarily associated with water loss from the extracellular fluid. As water is lost the sodium concentration of the remaining fluid increases. When water is drunk, it moves across the membrane lining the gut into the blood thereby decreasing the sodium concentration—osmolarity—of the blood. In turn, the cells of the hypothalamus take on water and return to their normal size. This time water moves back into these cells via osmosis in the opposite direction. 

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