Brain transport systems

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Synaptic vesicles isolated from brain exhibit four distinct vesicular neurotransmitter transport activities one for monoamines, a second for acetylcholine, a third for the inhibitory neurotransmitters GABA and glycine, and a fourth for glutamate [1], Unlike Na+-dependent plasma membrane transporters, the vesicular activities couple to a proton electrochemical gradient (A. lh+) across the vesicle membrane generated by the vacuolar H+-ATPase ( vacuolar type proton translocating ATPase). Although all of the vesicular transport systems rely on ApH+, the relative dependence on the chemical and electrical components varies (Fig. 1). The... 

Stoll J, Wadhwani KC, Smith QR. Identification of the cationic amino acid transporter (System y+) of the rat blood-brain barrier. ) Neurochem 1993 60 1956-1959. 

Tadayoni, B.M., Friden, P.M., Walus, L.R., and Musso, G.F. (1993) Synthesis in vitro kinetics, and in vivo studies on protein conjugates of AZT Evaluation as a transport system to increase brain delivery. Bioconjugate Chem. 4, 139-145. 

Distortion of the plasma aminogram in individuals with an aminoaciduria also may lead to a relative failure of brain protein synthesis. Thus, in mice with a deficiency of phenylalanine hydroxylase, the blood concentration of phenylalanine is more than 20 times greater than the control value, leading to partial saturation of the transport system and a diminution in the brain level of neutral amino acids other than phenylalanine. Rates of protein synthesis were concomitantly reduced [8]. 

The transport behavior of Li+ across membranes has been the focus of numerous studies, the bulk of which have concentrated upon the human erythrocyte for which the Li+ transport pathways have been elucidated and are summarized below. The movement of Li+ across cell membranes is mediated by transport systems which normally transport other ions, therefore the normal intracellular and subcellular electrolyte balance is likely to be disturbed by this extra cation. Additionally, Li+ has been shown to increase membrane phospholipid unsaturation in rat brain, leading to enhanced fluidity in the membrane, which could have repercussions for membrane-associated proteins and for membrane transport properties. 

Medication Transportation System. If the brain, the spinal cord, and the nerves make up the body s communication system, then the heart, blood vessels, and blood are the body s transportation system. Blood carries oxygen and nutrients to the organs and then returns the wastes for disposal. Medications use this same internal highway system to travel throughout the body. 

Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Para-chloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called "serotonin syndrome", which in animals is associated with abnormal movements, body posture and temperature. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Though drugs appear to cross the blood-brain barrier by passive diffusion, transporter systems in the blood-brain barrier pump drugs back out into the systemic circulation. As in the gut, the Pgp transporter system is the primary active transporter in the blood-brain barrier identified to date. This ATP-dependent transporter system picks up substrates that have crossed the capillary endothelial cells and transports them back to the systemic circulation, limiting their penetration into the CNS. Thus, not only are the physicochemical properties of the drug a determinant for penetration into the CNS but penetration also depends on whether the drug is a substrate for the Pgp transporter system. 

FDG is readily taken tip by this transport system, although the extent of uptake can be influenced by the concentration of plasma glucose, which competes with FDG for uptake. The efficiency of transport across the blood brain barrier is such that blood flow is generally not limiting for tracer delivery but the potential for a drug to have a direct vascular effect that influences tracer delivery should be considered. 

Because of the proliferation of adrenergic synapses in the CNS and the permeability of many of the following drugs into the brain tissue due to inherent lipophilicity or transport systems, several will be psychoactive as well as peripherally active. 

Consequently, many foreign compounds achieve the same concentration in fetal as in maternal plasma. However, if metabolism in utero converts the compound into a more polar metabolite, accumulation may occur in the fetus. Despite extensive blood flow (16% cardiac output 0.5 mLmin 1g 1 of tissue), entry of foreign compounds into the brain takes place much less readily than passage into other tissues. Hence, the term "blood-brain barrier." Ionized compounds will not penetrate the brain in appreciable quantities unless they are carried by active transport systems. The reasons for this are as follows ... 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

---