Enhanced Brain Delivery of Amino Acids and Peptides Through the Use of Redox Targeting Systems

  • Marcus E. Brewster
  • Wesley R. Anderson
  • Nicholas Bodor
Part of the Advances in Behavioral Biology book series (ABBI, volume 40)

Abstract

Many central diseases, including amino acid and neuropeptide deficiencies, are potentially treatable using replacement therapy. Unfortunately, delivery of the appropriate agents to the central nervous system is a highly complex undertaking due to an interfacial barrier of a vascular derivative termed the blood-brain barrier (BBB).1–3 The cerebral microvasculature differs in several important respects from those capillaries present in the periphery. Firstly, the endothelial cells which comprise the cerebral microvessels are tightly joined to one another.4,5 This unique architecture prevents the bulk movement of materials between cells and forces compounds to diffuse directly through the phospholipid cell membrane if they are to gain access to the brain parenchyma. Since only those agents with sufficient affinity for the lipid membranes will penetrate the BBB, hydrophilic molecules, including many drugs, are excluded.6 Other distinguishing features of cerebral capillaries are that they are not fenestrated and that they maintain a vesicular transport system of relatively low activity. These functions substantially restrict generalized movement of materials into the CNS and have clearly evolved to protect the delicate environment necessary for optimal neural functioning.

Keywords

Testosterone Angiotensin Estradiol Cyclosporin Meningitis 

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References

  1. 1.
    E. Neuwelt, “Implications of the Blood-Brain Barrier and Its Manipulation”, Plenum Book Co., New York, NY (1989).CrossRefGoogle Scholar
  2. 2.
    S. Rapoport, “The Blood-Brain Barrier in Physiology and Medicine”, Raven Press, New York, NY (1976).Google Scholar
  3. 3.
    W. Pardridge, J. Connor and I. Crawford, Permeability changes in the blood-brain barrier:causes and consequences. CRC Crit. Rev. Toxicol., 3: 159 (1975).CrossRefGoogle Scholar
  4. 4.
    T. Reese and M. Karnovsky, Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell. Biol. 34: 207 (1967).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Brightman and T. Reese, Junctions between intimately opposed cell membranes in the vertebrate brain. J. Cell. Biol. 40: 648 (1969).PubMedCrossRefGoogle Scholar
  6. 6.
    V. Levin, Relationship of octanol/water partition coefficients and molecular weight to rat brain capillary permeability. J. Med. Chem. 23: 682 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    E. Levin, Are the terms blood-brain barrier and brain capillary permeability synonymous ? Expl. Eve Res., Suppl. 25: 191 (1977).CrossRefGoogle Scholar
  8. 8.
    W. Pardridge, Transport of nutrients and hormones through the blood-brain barrier. Diabetologia 20: 246 (1981).PubMedCrossRefGoogle Scholar
  9. 9.
    N. Greig, S. Momma, D. Sweeney, Q. Smith and S. Rapoport, Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system. Cancer Res. 47: 1571 (1987).PubMedGoogle Scholar
  10. 10.
    J. Jankovic, Parkinson’s disease:recent advances in therapy. Southern Med. J., 81: 1021 (1988).PubMedCrossRefGoogle Scholar
  11. 11.
    L. Roland In “Marritt’s Textbook of Neurology” Lea and Febiger, ed., Philadelphia, PA (1984).Google Scholar
  12. 12.
    J. Martin and J. Gusella, Huntington’s disease:pathogenesis and management. New Eng. J. Med. 35: 1267 (1986).Google Scholar
  13. 13.
    B. Meldrum, Epilepsy and γ-aminobutyric acid-mediated inhibition. Int. Rev. Neurobiol. 17: 1 (1975).PubMedCrossRefGoogle Scholar
  14. 14.
    H. Feltkamp, K. Meurer and F. Godchardt, Tryptophan-induced lowering of blood pressure and charges of serotonin uptake by platelets in patients with essential hypertension. Klin. Wochenschr. 62: 1115 (1984).PubMedCrossRefGoogle Scholar
  15. 15.
    W. Wolf and D. Kuhn, Effect of L-tryptophan on blood pressure in normotensive and hypertensive rats. J. Pharmacol. Exp. Therap. 230: 324 (1984).Google Scholar
  16. 16.
    B. Roos and G. Steg, The effect of 3, 4-dihydroxyphenylalanine and 4-hydroxytryptophan on rigidity and tremor induced by reserpine, chlorpromazine and phenoxybenzamine. Life Sci. 3: 351 (1964).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Barbeau, P. Singh, P. Gaudreau and M. Joubert, Effect of 3, 4-dimethoxyphenylamine injections on the concentration of catecholamines in the rat brain. Rev. Can. Biolo. 3: 229 (1965).Google Scholar
  18. 18.
    A. Krantis, The involvement of GAB A transaminase in the blood-brain barrier to radiolabelled GABA. Acta Neuropathol. 64: 61 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    W. M. Pardridge, Strategies for drug delivery through the blood-brain barrier. In: “Directed Drug Delivery”, V. J. Stella (ed.), Humana Press, Clifton, NJ (1985).Google Scholar
  20. 20.
    G. Meisenberg, W.H. Simmons, Peptides and the blood-brain barrier, Life Sci. 32: 2611 (1983).PubMedCrossRefGoogle Scholar
  21. 21.
    H. Akil, S.J. Watson, E. Young, M.E. Lewis, H. Khachaturian, and J. M. Walker, Endogenous opioids: biology and function, Ann. Rev. Neurosci. 7: 223 (1984).PubMedCrossRefGoogle Scholar
  22. 22.
    H. Takagi, H. Shiomi, H. Ueda, H. Amano, A novel analgesic dipeptide from bovine brain is a possible met-enkephalin releaser, Nature. 282: 410 (1979)PubMedCrossRefGoogle Scholar
  23. 23.
    G. G. Yarbrough, N. Pomara, The therapeutic potential of thyrotropin-releasing hormone (TRH) in Alzheimer’s disease (AD), Prog. Neuro-Pharmacol. Biol. Psychiatr. 9: 285 (1985).Google Scholar
  24. 24.
    D. Ganten, K. Fuxe and M. I. Phillips, In “Frontiers of Neuroendocrinology”, Vol. 5, Raven Press, New York (1978).Google Scholar
  25. 25.
    S.S. Yen, Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs, Fertil. Steril. 39: 257 (1983).Google Scholar
  26. 26.
    E. M. Cornford, L. D. Braun, P.D. Crane, W. H. Oldendorf, Blood-brain barrier restriction of peptides and the low uptake of enkephalins, Endocrinology, 103: 1297 (1978).PubMedCrossRefGoogle Scholar
  27. 27.
    W. H. Oldendorf, Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard., Brain Res., 24: 372 (1970).PubMedCrossRefGoogle Scholar
  28. 28.
    P. Schelling, J.S. Hutchinson, U. Ganten, G. Sponer, D. Ganten, Impermeability of the blood-cerebrospinal fluid barrier for angiotensin II in rats, Clin.Sci. Mol. Med. 51 :S399(1976). Google Scholar
  29. 29.
    B.V. Zlokovic, J. B. Mackic, B. Djuricic, H. Davson, Kinetic analysis of leucineenkephalin cellular uptake at the luminal side of the blood-brain barrier of an in situ perfused guinea-pig brain. J. Neurochem. 53: 1333 (1989).PubMedCrossRefGoogle Scholar
  30. 30.
    D. L. Hammond, Intrathecal administration: methodological considerations, Prog. Brain. Res. 77: 313 (1988).CrossRefGoogle Scholar
  31. 31.
    H. J. Reiser, H. M. Pinedo, Cancer chemotherapy: alternative routs of drug administration, Cancer Drug. Deliv. 2: 147 (1985).Google Scholar
  32. 32.
    R. E. Harbaugh, Novel CNS-directed drug delivery systems in Alzheimer’s disease and other neurological disorders. Neurobiol. Aging 10: 623 (1989).PubMedCrossRefGoogle Scholar
  33. 33.
    M. E. Brewster, Non-invasive drug delivery to the brain. Neurobiol. Aging 10: 638 (1989).PubMedCrossRefGoogle Scholar
  34. 34.
    T. L. Musat, J. Taft, D. Kasdon and I.M.D. Jackson, Prolonged intrathecal infusion of thyrotropin-releasing hormone in amyotrophic lateral sclerosis. Ann. NY Acad. Sci. 531: 187 (1988).CrossRefGoogle Scholar
  35. 35.
    J.C. Cradock, L.M. Kleinman and J. P. Davignon, Intrathecal injections - a review of pharmaceutical factors. Bull. Parent. Drug. Assoc. 31: 237 (1977).Google Scholar
  36. 36.
    R.I. Macey, Mathematical models of membrane transport processes. Physiology of membrane disorders. Plenum Press, New York (1978).Google Scholar
  37. 37.
    D. G. Paplack, A. W. Blayer and M. E. Horowitz, In “Neurobiology of Cerebrospinal Fluid”, Plenum Press, New York 1981.Google Scholar
  38. 38.
    R. B. Aird, A study of intrathecal, cerebrospinal fluid-to-brain exchange. Exp. Neurol 86: 342 (1984).PubMedCrossRefGoogle Scholar
  39. 39.
    S. I. Rapaport, M. Ohata and E.D. London, Cerebral blood flow and glucose utilization following opening of the blood-brain barrier and during maturation of the rat brain. Fed. Proc. Am. Soc. Expl. Biol. 40: 2322 (1981).Google Scholar
  40. 40.
    J. D. Fenstermacher and A. L. Cowles. Theoretic limitations of intracarotid infusions in brain tumor chemotherapy, Cancer Treat. Rep., 61: 519 (1977).PubMedGoogle Scholar
  41. 41.
    K. Ohno, W. R. Fredericks and S. I. Rapoport, Osmotic opening of the blood-brain barrier to methatrexate in the rat. Surg. Neurol. 12: 323 (1979).PubMedGoogle Scholar
  42. 42.
    E. A. Neuwelt, E. P. Frankel and M. K. Gummerlock, Developments in the diagnosis and treatment of primary CNS lymphoma. Cancer 58: 1609 (1986).PubMedCrossRefGoogle Scholar
  43. 43.
    E. A. Neuwelt, and S. I. Rapaport Modification of the blood-brain barrier in the chemotherapy of malignant brain tumors. Fed. Proc. 43: 214 (1984).PubMedGoogle Scholar
  44. 44.
    N. Bodor, Novel approaches to prodrug design. Drugs Fut. 6: 165 (1981).Google Scholar
  45. 45.
    N. Bodor and J. Kaminski, Prodrug and site-specific chemical delivery systems. Ann. Repts. Med. Chem. 22: 303 (1987).CrossRefGoogle Scholar
  46. 46.
    N. Bodor, Prodrugs versus soft drugs In “Design of Prodrugs” H. Bundgard (ed.) Elsevier, Amsterdam (1985).Google Scholar
  47. 47.
    V. A. Levin, Relationship of octanol/water partition coefficients and molecular weight to rat brain capillary permeability. J. Med. Chem. 23: 682 (1980).PubMedCrossRefGoogle Scholar
  48. 48.
    J. D. Fenstermacher, Current models of blood brain transfer. Trends Neurosci. 8: 449 (1980).CrossRefGoogle Scholar
  49. 49.
    J. Garrod, Potential hazards of the prodrug approach. Chem. Ind. 11: 458 (1980).Google Scholar
  50. 50.
    P. L. Hoffman, R. Walter, M. Bulat, An enzymatically stable peptide with activity in the central nervous system: its penetration through the blood-CSF barrier. Brain Res. 122: 87 (1977).PubMedCrossRefGoogle Scholar
  51. 51.
    W. T. Cefalu, W. M. Pardridge, Restrictive transport of a lipid-soluble peptide (cyclosporin) through the blood-brain barrier. J. Neurochem. 45: 1954 (1985).PubMedCrossRefGoogle Scholar
  52. 52.
    D. J. Begley, L. K. Squires, B. V. Zlokovic, D. M. Mitrovic, C. C. Hughes, P. A. Revest, J. Greenwood, Permeability of the blood-brain barrier to the immunosuppressive cyclic peptide cyclosporin A, J. Neurochem. 55: 1222 (1990).PubMedCrossRefGoogle Scholar
  53. 53.
    W. M. Pardridge, Strategies for drug delivery through the blood-brain barrier. Neurobiol. Aging 10: 636 (1989).PubMedCrossRefGoogle Scholar
  54. 54.
    F. Ito, S. Ito, N. Shimizu, Transmembrane delivery of polypeptide hormones bypassing the intrinsic cell surface receptors: a conjugate of insulin with alpha 2-macroglobulin (alpha 2M) recognizing both insulin and alpha 2M receptors and its biological activity in relation to endocytic pathways. Mol. Cell. Endocr. 36: 165 (1984).CrossRefGoogle Scholar
  55. 55.
    N. Bodor and M. E. Brewster, Problems of delivery of drugs to the brain. Pharm. Ther. 19: 337 (1983).CrossRefGoogle Scholar
  56. 56.
    N. Bodor, H. H. Farag and M. E. Brewster, Site-specific, sustained release of drugs to the brain. Science 214: 1370 (1981).PubMedCrossRefGoogle Scholar
  57. 57.
    N. Bodor, Redox drug delivery for targeting drugs to the brain. Ann. NY Acad. Sci. 507: 289 (1987).PubMedCrossRefGoogle Scholar
  58. 58.
    N. Bodor and J. W. Simpkins, Redox delivery system for brain-specific, sustained release of dopamine. Science 221: 65 (1983).PubMedCrossRefGoogle Scholar
  59. 59.
    J. W. Simpkins, N. Bodor and A. Enz, Direct evidence for brain-specific release of dopamine from a redox delivery system. J. Pharm. Sci. 74: 1033 (1985).PubMedCrossRefGoogle Scholar
  60. 60.
    K. Matsuyama, C. Yamashita, A. Noda, S. Goto, H. Nodo, Y. Ichimaru and Y. Gomita. Evaluation of isonicotinoyl-γ-aminobutyric acid (GABA) and nicotinoyl-GABA as prodrugs of GABA. Chem. Pharm. Bull. 32: 4089 (1984).PubMedCrossRefGoogle Scholar
  61. 61.
    P. A. Woodard, D. Winwood, M. E. Brewster, K. Estes and N. Bodor, Improved delivery through biological membranes. 21. Brain-targeted anticonvulsive agents. Drug Des. Del. 6: 15 (1990).Google Scholar
  62. 62.
    W. R. Anderson, J. W. Simpkins, P. A. Woodard, D. Winwood, W.C. Stern and N. Bodor, Anxiolytic activity of a brain delivery system for GABA. Psychopharmacol. 92: 157 (1987).Google Scholar
  63. 63.
    E. Pop, W. R. Anderson, K. Prokai-Tatrai, M. E. Brewster, M. Fregly and N. Bodor, Antihypertensive activity of redox derivatives of tryptophan. J. Med. Chem. 33: 2216 (1990).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Marcus E. Brewster
    • 1
    • 2
  • Wesley R. Anderson
    • 1
    • 2
  • Nicholas Bodor
    • 1
    • 2
  1. 1.Pharmatec, Inc.AlachuaUSA
  2. 2.Center for Drug Discovery, College of PharmacyUniversity of FloridaGainesvilleUSA

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