Blood-brain barrier specialized transport systems

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

The term blood-brain barrier (BBB) refers to the special obstacle that drugs encounter when trying to enter the brain from the circulatory system. The difference between the brain and other tissues and organs is that the capillaries in the brain do not have pores for the free flow of small molecules in the interstitial fluid of the brain. To enter the interstitial fluid, all molecules must cross a membrane. This design is a protective measure to defend the brain from unwanted and potentially hazardous xenobiotics. Traditionally, drugs that target the brain or central nervous system (CNS) cross the BBB by passive diffusion. Transport by carrier proteins across the BBB is becoming better understood but remains an area of active research. 

In general, the blood-brain barrier (BBB) is only permeable to lipophilic molecules of molecular weight <600 Da, while even small water-soluble molecules generally cannot be transported [21]. This would preclude the direct delivery of ASO to the brain from the systemic circulation without the assistance of specialized drug delivery systems. 

DOPA decarboxylase, a pyridoxal phosphate-requiring enzyme, catalyzes the synthesis of dopamine from DOPA. Dopamine is produced in neurons found in certain structures in the brain. It is believed to exert an inhibitory action within the central nervous system. Deficiency in dopamine production has been found to be associated with Parkinson s disease, a serious degenerative neurological disorder (Special Interest Box 14.3). The precursor l-DOPA is used to alleviate the symptoms of Parkinson s disease because dopamine cannot penetrate the blood-brain barrier. (The blood-brain barrier protects the brain from toxic substances. Many polar molecules and ions cannot move from blood capillaries, although most lipid-soluble substances readily pass across. The blood-brain barrier consists of connective tissue and specialized cells called astrocytes that envelop the capillaries.) Once l-DOPA is transported into appropriate nerve cells, it is converted to dopamine. 

Passive diffusion directly through the cell membrane highly depends on the solubility of the molecule in the lipid bilayer, which will be the focus of the next section. Some barriers in the body are specially modified to enhance or limit the transport of molecules through particular barriers. For example, relatively large gaps between cells in the small intestinal wall and fenestrations in kidney capillaries both increase the rate of transport across these barriers for many molecules. Conversely, capillaries in the central nervous system (GNS) have especially thick walls and extremely small gaps between cells, which limits the passage of molecules into the GNS and represents some of the factors responsible for the blood-brain barrier. 

It has been reported that GABA was absorbed in the gastrointestinal tract as a specialized transport mechanism which obeys Michaelis-Menten and first-order kinetics [52]. Since the blood-brain barrier is impermeable to GABA [53], the hypotensive effect of peripherally administered GABA is due to the actions of the peripheral nervous system and those of several... 

This correlation is useful for rapid estimation of the blood-brain barrier permeability. More accurate estimation can be obtained by examining other physical characteristics of the compound, such as cross-sectional area and critical micelle concentration [27] (Figure 5.28). Because of the extremely low permeability of brain capillaries to most molecules, brain endothelial cells have a variety of specialized transport systems—including transporters for glucose, amino acids, insulin, and transferrin—that enable essential molecules to move from the blood into the brain extracellular space. Useful reviews of the blood-brain barrier are available [28, 29]. 

Capillary endothelial cells possess specialized transport proteins which permit the passage of specific molecules. The endothelial cells of the blood-brain barrier have a number of specialized transport systems that are essential for brain function (see Chapter 5 and [56, 57]). Sometimes, these transport systems can be deceived by creating or finding agents that resemble the native substrate for the transport protein, but are modified to possess a desired biological activity. 

Folate transport across the blood-brain barrier. The active transport of folate into the brain takes place in the epithelial cells of the choroid plexus. 5-Methyl tetrahydrafolate (5-MTHF), the main form of folate in serum, is bound to the high affinity folate receptors on the epithehal cells and transported into the cells. Endosomes and transport proteins are involved in the intracellular transfer. Finally, the reduced folate carriers on the brush border deliver 5-MTHF into the CSF. This folate transport system is energy dependent and saturable. It stabilizes cerebrospinal folate concentration whether the serum folate is low or high. Thus, the transport system has an important homeostatic function for brain folate. Likewise, vitamins Bi, B2, Be, B7 and B12 have specialized transport systems into the CSF. 

---