Blood-brain barrier transport mechanisms

Aschner M, Aschner JL. 1990. Mercury neurotoxicity mechanisms of blood-brain barrier transport. Neurosci Biobehav Rev 14 169-176. 

The particular way in which the walls of the blood vessels in the central nervous system are constructed results in their being impermeable to many substances, thereby limiting the ability of molecules to pass from the blood into the brain. This phenomenon is called the blood-brain barrier. Molecules may cross the blood-brain barrier by mechanisms of active transport, or by being sufficiently lipid soluble that they can diffuse through the hydrophobic core of the lipid membranes that form the boundaries of the cells composing the blood-brain barrier. Most psychoactive drugs are sufficiently lipid soluble that they can pass from the blood into the brain by passive diffusion. 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase. Although histamine is present in plasma, it does not penetrate the blood-brain barrier, such that histamine concentrations in the brain must be maintained by synthesis. With a value of 0.1 mmol/1 for L-histidine under physiological conditions, HDC is not saturated by histidine concentrations in the brain, an observation that explains the effectiveness of large systemic doses of this amino acid in raising the concentrations of histamine in the brain. The essential amino acid L-histidine is transported into the brain by a saturable, energy-dependent mechanism [5]. Subcellular fractionation studies show HDC to be localized in cytoplasmic fractions of isolated nerve terminals, i.e. synaptosomes. 

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

An intact CNS is critical to the well-being of a person. Nature has gone to a good deal of trouble to protect the CNS from damage, both external and internal. The brain is protected from external trauma by the bony structure we call the skull. The spine is similarly protected by the bony spinal column. The CNS is also protected by the blood-brain barrier against penetration by molecules that might prove a problem. There are special facilitated transport mechanisms for specific molecules required by the CNS but which cannot penetrate the blood-brain barrier. 

In the central nervous system (brain and spinal cord), capillary endo-theUa lack pores and there is little transcytotic activity. In order to cross the blood-brain barrier, drugs must diffuse transcellularly, i.e., penetrate the luminal and basal membrane of endothelial cells. Drug movement along this path requires specific physicochemical properties (p. 26) or the presence of a transport mechanism (e.g., L-dopa, p. 188). Thus, the blood-brain barrier is permeable only to certain types of drugs. 

Active efflux transporters also exist in the placenta, analogous to the gut and blood-brain barrier. These are Pgp, multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). These transport proteins are located in many tissues but also appear to be expressed in the placenta. Though the substrate specificities of these proteins have not been completely described, they appear to function as efflux transporters, moving endogenous and exogenous chemicals from the placental cells back to the systemic circulation. In this way, they serve as a mechanism to protect the fetus from exposure to unintended chemicals. 

Fig. (2). Hypothesized mechanisms of neurotoxicity of MPTP. After injection of MPTP, its native form crosses the blood brain barrier (BBB) and is oxidized by monoamine oxidase B (MAO-B) into MPP+. This metabolite is transported and concentrated into nigrostriatal dopamine and exerts a neurotoxic effect...

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