Brain dopamine delivery

Zhigaltev FV, Kaplun AP, Kucheryanu VG, et al. Liposomes containing dopamine entrapped in response to transmembrane ammonium sulfate gradient as carrier system for Dopamine delivery into the brain of Parkinsonian mice. J Liposome Res 2001 11 55-71. 

Frey WH, Liu J, Thorne RG, et al Intranasal delivery of 125 1-labeled nerve growth factor to the brain via the olfactory route, in Research Advances in Alzheimer s Disease and Related Disorders. Edited by Iqbal K, Mortimer JA, Winblad B, et al. Chichester, England, Wiley, 1995, pp 329-335 Eriedman E, Gershon S Effect of lithium on brain dopamine. Nature 243 520-521, 1973... 

Zhigaltsev, I. V., Kaplun, A. P, Kucheryanu, V. G., Kryzhanovsky, G. N., Kolomeichuk, S. N., Shvets, V. I., and Yurasov, V. V. (2001), Liposomes containing dopamine entrapped in response to transmembrane ammonium sulfate gradient as carrier system for dopamine delivery into the brain of parkinsonian mice, J. Liposome Res., 11,55-71. 

Bodor N, Farag HH. Improved delivery through biological membranes. 13. Brain specific delivery of dopamine with a dihydropyridinne-reversible-pyridinium salt type redox delivery system. J Med Chem 1983 26 528-534. 

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson s disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids [56]. Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma. 

The toxin 6-OHDA does not cross the blood brain barrier after peripheral administration in the adult animal, and so must be administered centrally in order to yield effective lesions. This restriction does not apply in neonates. Thus, 6-OHDA can produce profound depletions of central catecholamines when administered subcutaneously or intracisternally to neonatal rats or mice (Breese and Traylor, 1971). Moreover, greater selectivity for individual amine pathways can be achieved by refinements of the route of delivery or by pharmacological manipulation, and different protocols of administration can allow relatively selective depletions. For example, several small repeated injections of 6-OHDA spare dopamine and preferentially deplete dopamine, whereas dopamine toxicity after a single large injection can be enhanced by pargyline treatment, in particular if the noradrenaline depletion is concurrently blocked with pargyline (Breese and Traylor, 1971 Cooper et al., 1973 Smith et al., 1973 Luthman et al., 1989). 

Aminobutyramide of /V-glucosyl amine, (III), prepared by Miller (4) was effective as a blood-brain barrier using conjugate for delivery of the neuroactive agents such as serotonin, dopamine, and enkephalin. 

Bodor N, Simpkins JW. Redox delivery system for brain-specific, sustained-release of dopamine. Science 1983 221 65-67. 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

Simpkins, J., N. Bodor, and A. Enz, Direct evidence for brain-specific release of dopamine from a redox delivery system. Journal of Pharmaceutical Sciences, 1985, 74, 1033-1036. 

Trapani A, et al. Characterization and evaluation of chitosan nanoparticles for dopamine brain delivery. Int J Pharm. 2011 419(l-2) 296-307. 

Peptides and small molecules may use specific transporters expressed on the luminal and basolateral sides of the endothelial cells to cross into the brain. So far, at least eight different nutrient transporters have been identified to transport a group of nutrients with similar structures. Drugs can be modified to closely mimic the endogenous carrier substrates of these transporters and be transported through the specific transporter-mediated transcytosis. Dopamine can be used to treat Parkinson s disease, but itself is nonbrain penetrant. Instead, dopamine s metabolic precursor, L-Dopa, if delivered by a neutral amino acid carrier through its transporter at the BBB, shows a clear clinical benefit on patients with Parkinson s disease [6,121]. To use a BBB transporter for drug delivery, several important factors must... 

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