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Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain Ischemia Following Delayed Intravenous Administration of Neurotrophins

  • William M. Pardridge
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 513)

Abstract

The blood-brain barrier (BBB) is the rate-limiting step in the translation of neurotrophin neuroscience into clinically effective neurotherapeutics. Since neurotrophins do not cross the BBB, these proteins cannot be used for neuroprotection following intravenous administration, and it is not feasible to administer these molecules by intra-cerebral injection in human stroke. The present studies describe the development of the chimeric peptide brain drug targeting technology and the use of brain-derived neurotrophic factor (BDNF) chimeric peptides in either global or regional brain ischemia. The BDNF chimeric peptide is formed by conjugation of BDNF to a monoclonal antibody (MAb) to the BBB transferrin receptor, and the MAb acts as a molecular Trojan Horse to ferry the BDNF across the BBB via transport on the endogenous BBB transferrin receptor. High degrees of neuroprotection in transient forebrain ischemia, permanent middle cerebral artery occlusion, or reversible middle cerebral artery occlusion are achieved with the delayed intravenous administration of BDNF chimeric peptides. In contrast, no neuroprotection is observed following the intravenous administration of unconjugated BDNF, because the neurotrophin does not cross the BBB in vivo.

Keywords

Neurotrophic Factor Middle Cerebral Artery Occlusion Vasoactive Intestinal Peptide Brain Uptake Transient Forebrain Ischemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Pardridge WM. Brain Drug Targeting: The Future of Brain Drug Development. Cambridge: Cambridge University Press, 2001:1–370.CrossRefGoogle Scholar
  2. 2.
    Pardridge WM. CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70:1781–1792.PubMedCrossRefGoogle Scholar
  3. 3.
    Hefti F. Pharmacology of neurotrophic factors. Annu Rev Pharmacol Toxicol 1997;37:239–267.PubMedCrossRefGoogle Scholar
  4. 4.
    Apfel S. Clinical Applications of Neurotrophic Factors. New York: Lippincott-Raven, 1997:5.Google Scholar
  5. 5.
    Kordower JH, Palfi S, Chen E-Y et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parksinson s disease. Annal Neurol 1999; 46:419–424.PubMedCrossRefGoogle Scholar
  6. 6.
    Yan Q, Matheson C, Sun J et al. Exp Neurol 1994; 127:23–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Pardridge WM. Peptide Drug Delivery to the Brain. New York: Raven Press, 1991:1–357.Google Scholar
  8. 8.
    Winkler J, Ramirez GA, Kuhn HG et al. Reversible schwann cell hyperplasia and sprouting of sensory and sympathetic neuntes after intraventricular administration of nerve growth factor. Ann Neurol 1997; 41:82–93.PubMedCrossRefGoogle Scholar
  9. 9.
    Yamada K, Kinoshita A, Kohmura E et al. Basic fibroblast growth factor prevents thalamic degeneration after cortical infarction. J Cereb Blood Flow Metabol 1991; 11:472–478.CrossRefGoogle Scholar
  10. 10.
    Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. 1 Neurochem 1985; 44:1771–1778.Google Scholar
  11. 11.
    Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabol 1987; 36:892–895.CrossRefGoogle Scholar
  12. 12.
    Duffy KR, Pardridge WM, Rosenfeld RG. Human blood-brain barrier insulin-like growth factor receptor. Metabol 1988; 37:136–140.CrossRefGoogle Scholar
  13. 13.
    Golden PL, Maccagnan TJ, Pardridge WM. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest 1997; 99:14–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Clemmons DR. Insulinlike growth factor binding proteins. Trends Endocrinol Metabol 1990; 1:412–417.CrossRefGoogle Scholar
  15. 15.
    Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987; 420:32–38.PubMedCrossRefGoogle Scholar
  16. 16.
    Bickel U, Kang Y-S, Yoshikawa T et al. In vivo demonstration of subcellular localization of anti-transferrin receptor monoclonal antibody-colloidal gold conjugate within brain capillary endothelium. J Histochem Cytochem 1994; 42:1493–1497.PubMedCrossRefGoogle Scholar
  17. 17.
    Skarlatos S, Toshikawa T, Pardridge WM. Transport of [125I] transferrin through the rat blood-brain barrier in vivo. Brain Res 1995; 683:164–171.PubMedCrossRefGoogle Scholar
  18. 18.
    Fishman JB, Rubin JB, Handrahan JV et al. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res 1987; 18:299–304.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang Y, Pardridge WM. Rapid transferrin effliix from brain to blood across the blood-brain barrier. J Neurochem 2001; 76:1597–1600.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol. 2001; 114:168–172.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee HJ, Engelhardt B, Lesley J et al. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through the blood-brain barrier in the mouse. J Pharmacol Exp Ther 2000; 292:1048–1052.PubMedGoogle Scholar
  22. 22.
    Pardridge WM, Kang Y-S, Buciak JL et al. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vivo and rapid transcytosis through the blood-brain barrier in vivo in the primate. Phann Res 1995; 12:807–816.CrossRefGoogle Scholar
  23. 23.
    Coloma MJ, Lee Hi, Kurihara A et al. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Phann Res 2000; 17:266–274.CrossRefGoogle Scholar
  24. 24.
    Penichet ML, Kang Y-S, Pardridge WM et al. An anti-transferrin receptor antibody-avidin fusion protein serves as a delivery vehicle for effective brain targeting in an animal model. Initial applications in antisense drug delivery to the brain. J Immunol 1999; 163:4421–4426.PubMedGoogle Scholar
  25. 25.
    Li JY, Sugimura K, Boado RJ et al. Genetically engineered brain drug delivery vectors Cloning, expression, and in vivo application of an anti-transferrin receptor single chain antibody-streptavidin fusion gene and protein. Protein Engineer 1999; 12:787–796.CrossRefGoogle Scholar
  26. 26.
    Lee TJ-F, Saito A. Vasoactive intestinal polypeptide-like substance: the potential transmitter for cerebral vasodilation. Science 1984; 224:898–901.PubMedCrossRefGoogle Scholar
  27. 27.
    Said SI. Molecules that protect: the defense of neurons and other cells. J Clin Invest 1996; 97:2163–2164.PubMedCrossRefGoogle Scholar
  28. 28.
    Lindvall M, Owan C. Autonomic nerves in the mammalian choroid plexus and their influence on the formation of cerebrospinal fluid. J Cereb Blood Flow Metabol 1981; 1:245–266.CrossRefGoogle Scholar
  29. 29.
    Huffman L, Hedge GA. Effects of vasoactive intestinal peptide on thyroid blood flow and circulating thyroid hormone levels in the rat. Endocrinol 1986; 118:550–557.CrossRefGoogle Scholar
  30. 30.
    Wilson DA, O Neill JT, Said SI et al. Vasoactive intestinal polypeptide and the canine cerebral circulation. Circ Res 1981; 48:138–148.PubMedCrossRefGoogle Scholar
  31. 31.
    McCulloch J, Edvinsson L. Cerebral circulatory and metabolic effects of vasoactive intestinal polypeptide. Am J Physiol 1980; 238:H449–H456.PubMedGoogle Scholar
  32. 32.
    Bickel U, Yoshikawa T, Landaw EM et al. Pharmacologie effects in vivo in brain by vector-mediated peptide drug delivery. Proc Natl Acad Sci 1993; 90:2618–2622.PubMedCrossRefGoogle Scholar
  33. 33.
    Wu D, Pardridge WM. CNS pharmacologie effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analogue coupled to a blood-brain barrier drug delivery system. J Pharmacol Exp Ther 1996; 279:77–83.PubMedGoogle Scholar
  34. 34.
    Andersson M, Marie J-C, Carlquist M et al. The preparation of biotinyl-e-aminocaproylated forms of the vasoactive intestinal peptide (VIP) as probes for the VIP receptor. FEBS 1991; 282:35–40.CrossRefGoogle Scholar
  35. 35.
    Huffman LJ, Connors JM, Hedge GA. VIP and its homologues increase vascular conductance in certain endocrine and exocrine glands. Am J Physiol 1988; 254:435-E442.Google Scholar
  36. 36.
    Honig B, Nicholls A. Classical electrostatics in biology and chemistry. Science 1995; 268:1144–1149.PubMedCrossRefGoogle Scholar
  37. 37.
    Ibanez CF, Ebendal T, Barbany G et al. Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by biding to the trk gene product. Cell 1992; 69:329–341.PubMedCrossRefGoogle Scholar
  38. 38.
    Pardridge WM, Kang Y-S, Buciak JL. Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pharm Res 1994; 11:738–746.PubMedCrossRefGoogle Scholar
  39. 39.
    Abuchowski A, McCoy JR, Palczuk NC et al. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem 1977; 252:3582–3586.PubMedGoogle Scholar
  40. 40.
    Rosenberg MB, Hawrot E, Breakefield XO. Receptor binding activities of biotinylated derivatives of b-nerve growth factor. J Neurochem 1986; 46:641–648.PubMedCrossRefGoogle Scholar
  41. 41.
    Sakane T, Pardridge WM. Carboxyl-directed pegylation of brain-derived neurotrophic factor markedly reduces systemic clearance with minimal loss of biologic activity. Pharm Res 1997; 14:1085–1091.PubMedCrossRefGoogle Scholar
  42. 42.
    Pardridge WM, Wu D, Sakane T. Combined use of carboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenous administration. Pharm Res 1998; 15:576–582.PubMedCrossRefGoogle Scholar
  43. 43.
    Wu D, Kang Y-S, Bickel U et al. Blood-brain barrier permeability to morphine-G-glucoronide is markedly reduced compared to morphine. Drug Metabol Disp 1997; 25:768–771.Google Scholar
  44. 44.
    Smith M-L, Bendek G, Dahlgren N et al. Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 1984; 69:385–401.PubMedCrossRefGoogle Scholar
  45. 45.
    Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to brain. Proc Natl Acad.Sei USA 1999; 96:254–259.CrossRefGoogle Scholar
  46. 46.
    Preston E, Foster DO. Evidence for pore-like opening of the blood-brain barrier following forebrain ischemia in rats. Brain Res 1997; 4–10.Google Scholar
  47. 47.
    Longa EZ, Weinstein PR, Carlson S et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20:84–91.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang Y, Pardridge WM. Conjugation of brain-derived neurotrophic factor to a blood-brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. Brain Res 2001; 889:49–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Menzies SA, Betz AL, Hoff JT. Contributions of ions and albumin to the formation and resolution of ischemic brain edema. J Neurosurg 1993; 78:257–266.PubMedCrossRefGoogle Scholar
  50. 50.
    Albayrak S, Zhao Q, Siesjo BK et al. Effect of transient focal ischemia on blood-brain barrier permeability in the rat: correlation to cell injury. Acta Neuropathol 1997; 94:158–163.PubMedCrossRefGoogle Scholar
  51. 51.
    Schabitz W-R, Schwab S, Spranger M et al. Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats. J Cerb Blood Flow Metabol 1997; 17:500–506.CrossRefGoogle Scholar
  52. 52.
    Kaplan B, Brint S, Tanabe J et al. Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 1991; 22:1032–1039.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang Y, Pardridge WM. Neuroprotection in transient focal brain ischemia following delayed, intravenous administration of BDNF conjugated to a blood-brain barrier drug targeting system. Stroke 2001; 32:1378–1384.PubMedCrossRefGoogle Scholar
  54. 54.
    Schabitz WR, Sommer C, Zoder W et al. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and BcI-2 expression after temporary focal cerebral ischemia. Stroke 2000; 31:2212–2217.PubMedCrossRefGoogle Scholar
  55. 55.
    Kawai N, Keep RF, Betz AL. Hyperglycemia and the vascular effects of cerebral ischemia. Stroke 1997; 28:149–154.PubMedCrossRefGoogle Scholar
  56. 56.
    Pan W, Banks WA, Fasold MB et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacol 1998; 37:1553–1561.CrossRefGoogle Scholar
  57. 57.
    Kurihara A, Deguchi Y, Pardridge WM. Epidermal growth factor radiopharmaceuticals: IIlIn chelation, conjugation to a blood-brain barrier delivery vector via a biotin-polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors. Bioconj Chem 1999; 10:502–511.CrossRefGoogle Scholar
  58. 58.
    Bemelmans A-P, Horellou P, Pradier L et al. Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington s disease, as demonstrated by adenoviral gene transfer. Human Gene Ther 1999; 10:2987–2997.CrossRefGoogle Scholar
  59. 59.
    Kitagawa H, Sasaki C, Sakai K et al. Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents ischemic brain injury after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metabol 1999; 19:1336–1344.Google Scholar
  60. 60.
    McMenamin MM et al. A g34.5 mutant of herpes simplex I causes severe inflammation in the brain. Neurosci 1998; 83:1225–1237.CrossRefGoogle Scholar
  61. 61.
    Lawrence MS et al. Inflammatory responses and their impact on b-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus. Gene Ther 1999; 6:1368–1379.PubMedCrossRefGoogle Scholar
  62. 62.
    Shi N, Pardridge WM. Noninvasive gene targeting to the brain. Proc Natl Acad Sci USA 2000; 97:7567–7572.PubMedCrossRefGoogle Scholar
  63. 63.
    Mash DC, Pablo J, Flynn DD et al. Characterization and distribution of transferrin receptors in the rat brain. J Neurochem 1990; 55:1972–1979.PubMedCrossRefGoogle Scholar
  64. 64.
    Cosgrove L, Lovrecz GO, Verkuylen A et al. Purification and properties of insulin receptor ectodomain from large-scale mammalian cell culture. Protein Expression 1995; 6:789–798.CrossRefGoogle Scholar
  65. 65.
    Pardridge WM. Vector-mediated peptide drug targeting to the brain. In: Frokjaer S, Christrup L, Krogsgaard-Larsen P, eds. Peptide and Protein Drug Research. Munksgaard, Copenhagen: Alfred Benzon Symposium 43, 1998:381–396Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • William M. Pardridge
    • 1
  1. 1.Department of MedicineUCLA School of Medicine, Los Angeles

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