Skip to main content
Log in

Delivery of Neurotrophic Factors to the Central Nervous System

Pharmacokinetic Considerations

  • Review Articles
  • Drug Disposition
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Neurotrophic factors are proteins with considerable potential in the treatment of central nervous system (CNS) diseases and traumatic injuries. However, a significant challenge to their clinical use is the difficulty associated with delivering these proteins to the CNS. Neurotrophic factors are hydrophilic, typically basic, monomeric or dimeric proteins, mostly in the size range of 5 to 30 kDa. Neurotrophic factors potently support the development, growth and survival of neurons, eliciting biological effects at concentrations in the nanomolar to femtomolar range. They are not orally bioavailable and the blood-brain and blood-cerebrospinal fluid barriers severely limit their ability to enter into and act on sites in the CNS following parenteral systemic routes of administration. Most neurotrophic factors have short in vivo half-lives and poor pharmacokinetic profiles. Their access to the CNS is restricted by rapid enzymatic inactivation, multiple clearance processes, potential immunogenicity and sequestration by binding proteins and other components of the blood and peripheral tissues.

The development of targeted drug delivery strategies for neurotrophic factors will probably determine their clinical effectiveness for CNS conditions. Achieving significant CNS target site concentrations while limiting systemic exposure and distribution to peripheral sites of action will lessen unwanted pleiotropic effects and toxicity.

Local introduction of neurotrophic factors into the CNS intraparenchymally by direct injection/infusion or by implantation of delivery vectors such as polymer matrices or genetically modified cells yields the highest degree of targeting, but is limited by diffusion restrictions and invasiveness. Delivery of neurotrophic factors into the cerebrospinal fluid (CSF) following intracerebroventricular or intrathecal administration is less invasive and allows access to a much wider area of the CNS through CSF circulation pathways. However, diffusional and cellular barriers to penetration into surrounding CNS tissue and significant clearance of CSF into the venous and lymphatic circulation are also limiting. Unconventional delivery strategies such as intranasal administration may offer some degree of CNS targeting with minimal invasiveness.

This review presents a summary of the neurotrophic factors and their indications for CNS disorders, their physicochemical characteristics and the different approaches that have been attempted or suggested for their delivery to the CNS. Future directions for further research such as the potential for CNS disease treatment utilising combinations of neurotrophic factors, displacement strategies, small molecule mimetics, chimaeric molecules and gene therapy are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Table II
Fig. 2
Table III
Table IV
Table V

Similar content being viewed by others

References

  1. Crane GR. Liddell-Scott-Jones lexicon of classical greek. In: Crane GR, editor. The Perseus Project. Version 2.0 [online]. Available from URL: http://www.perseus.tufts.edu [Accessed 2001 Nov 5]

  2. Hefti F, Denton TL, Knusel B, et al. Neurotrophic factors: What are they and what are they doing? In: Loughlin SE, Fallon JH, editors. Neurotrophic factors. San Diego (CA): Academic Press, Inc., 1993: 25–49

    Google Scholar 

  3. Landreth GE. Growth factors. In: Siegel GJ, editor. Basic neurochemistry: molecular, cellular and medical aspects. 6th ed. Philadelphia (PA): Lippincott-Raven, 1999: 383–98

    Google Scholar 

  4. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987; 237: 1154–62

    Article  PubMed  CAS  Google Scholar 

  5. Cohen S, Levi-Montalcini R, Hamburger V. A nerve growth-stimulating factor isolated from sarcomas 37 and 180. Proc Natl Acad Sci U S A 1954; 40: 1014–8

    Article  PubMed  CAS  Google Scholar 

  6. Saragovi HU, Gehring K. Development of pharmacological agents for targeting neurotrophins and their receptors. Trends Pharmacol Sci 2000; 21: 93–8

    Article  PubMed  CAS  Google Scholar 

  7. Broadwell RD, Banks WA. Cell biological perspective for the transcytosis of peptides and proteins through the mammalian blood-brain fluid barriers. In: Pardridge WM, editor. The blood-brain barrier: cellular and molecular biology. New York: Raven Press, 1993: 165–99

    Google Scholar 

  8. Davson H, Segal MB. Physiology of the CSF and blood-brain barriers. Boca Raton (FL): CRC Press, 1996

    Google Scholar 

  9. Pardridge WM. Peptide drug delivery to the brain. New York: Raven Press, 1991

    Google Scholar 

  10. Kastin AJ, Pan W, Maness LM, et al. Peptides crossing the blood-brain barrier: some unusual observations. Brain Res 1999; 848: 96–100

    Article  PubMed  CAS  Google Scholar 

  11. Pardridge WM. Drug delivery to the brain. J Cereb Blood Flow Metab 1997; 17: 713–31

    Article  PubMed  CAS  Google Scholar 

  12. Pardridge WM. CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70: 1781–92

    Article  PubMed  CAS  Google Scholar 

  13. Langer R. Drug delivery and targeting. Nature 1998; 392 Suppl.: S5–10

    Google Scholar 

  14. Putney SD, Burke PA. Improving protein therapeutics with sustained-release formulations. Nat Biotechnol 1998; 16(2): 153–7

    Article  PubMed  CAS  Google Scholar 

  15. Prentis RA, Lis Y, Walker SR. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964–1985). Br J Clin Pharmacol 1988; 25: 387–96

    Article  PubMed  CAS  Google Scholar 

  16. Verrall M. Lay-offs follow suspension of clinical trials of protein. Nature 1994; 370: 6

    PubMed  CAS  Google Scholar 

  17. Loughlin SE. Neurotrophic factors. San Diego (CA): Academic Press Inc., 1993

    Google Scholar 

  18. Apfel SC, Water TRVD, Koszer S. Clinical applications of neurotrophic factors. Philadelphia (PA): Lippincott-Raven Publishers, 1997

    Google Scholar 

  19. Bregman BS, Broude E, McAtee M, et al. Transplants and neurotrophic factors prevent atrophy of mature CNS neurons after spinal cord injury. Exp Neurol 1998; 149(1): 13–27

    Article  PubMed  CAS  Google Scholar 

  20. Bregman BS, McAtee M, Dai HN, et al. Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat. Exp Neurol 1997; 148(2): 475–94

    Article  PubMed  CAS  Google Scholar 

  21. Grill R, Murai K, Blesch A, et al. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 1997; 17(14): 5560–72

    PubMed  CAS  Google Scholar 

  22. Ye JH, Houle JD. Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp Neurol 1997; 143(1): 70–81

    Article  PubMed  CAS  Google Scholar 

  23. Barinaga M. Neurotrophic factors enter the clinic. Science 1994; 264(5160): 772–4

    Article  PubMed  CAS  Google Scholar 

  24. Walsh G. Nervous excitement over neurotrophic factors. Biol Technol 1995; 13: 1167–71

    CAS  Google Scholar 

  25. Johnson JE. Neurotrophic factors. In: Zigmond MJ, Bloom FE, Landis SC, et al., editors. Fundamental neuroscience. San Diego (CA): Academic Press, 1999: 611–35

    Google Scholar 

  26. Glass DJ, Yancopoulos GD. The neurotrophins and their receptors. Trends Cell Biol 1993; 3: 262–7

    Article  PubMed  CAS  Google Scholar 

  27. Cordon-Cardo C, Tapley P, Jing SQ, et al. The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3. Cell 1991; 66(1): 173–83

    Article  PubMed  CAS  Google Scholar 

  28. Soppet D, Escandon E, Maragos J, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 1991; 65(5): 895–903

    Article  PubMed  CAS  Google Scholar 

  29. Swen JS, Flanagan TR, Wiggans TG. Assessing commercial potential of central nervous system delivery approaches. In: Flanagan TR, Emerich DF, Winn SR, editors. Methods in neurosciences. San Diego (CA): Academic Press, 1994: 485–98

    Google Scholar 

  30. Mufson EJ, Kroin JS, Sendera TJ, et al. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative disease. Prog Neurobiol 1999; 57: 451–84

    Article  PubMed  CAS  Google Scholar 

  31. Teng YD, Mocchetti I, Taveira-DaSilva AM, et al. Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. J Neurosci 1999; 19(16): 7037–47

    PubMed  CAS  Google Scholar 

  32. Cheng H, Cao Y, Olson L. Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 1996; 273(5274): 510–3

    Article  PubMed  CAS  Google Scholar 

  33. Fisher M, Meadows M-E, Do T, et al. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1995; 15: 953–9

    Article  PubMed  CAS  Google Scholar 

  34. Cuevas P, Carceller F, Munoz-Willery I, et al. Intravenous fibroblast growth factor penetrates the blood-brain barrier and protects hippocampal neurons against ischemia-reperfusion injury. Surg Neurol 1998; 49(1): 77–83

    Article  PubMed  CAS  Google Scholar 

  35. Teng YD, Mocchetti I, Wrathall JR. Basic and acidic fibroblast growth factors protect spinal motor neurones in vivo after experimental spinal cord injury. Eur J Neurosci 1998; 10(2): 798–802

    Article  PubMed  CAS  Google Scholar 

  36. Guo Q, Sebastian L, Sopher BL, et al. Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc Natl Acad Sci U S A 1999; 96(7): 4125–30

    Article  PubMed  CAS  Google Scholar 

  37. Eckenstein FP. Fibroblast growth factors in the nervous system. J Neurobiol 1994; 25(11): 1467–80

    Article  PubMed  CAS  Google Scholar 

  38. Lesser SS, Lo DC. CNTF II, I presume? Nat Neurosci 2000; 3(9): 851–2

    Article  PubMed  CAS  Google Scholar 

  39. Murphy M, Dutton R, Koblar S, et al. Cytokines which signal through the LIF receptor and their actions in the nervous system. Prog Neurobiol 1997; 52(5): 355–78

    Article  PubMed  CAS  Google Scholar 

  40. Yamakuni H, Minami M, Satoh M. Localization of mRNA for leukemia inhibitory factor receptor in the adult rat brain. J Neuroimmunol 1996; 70(1): 45–53

    Article  PubMed  CAS  Google Scholar 

  41. Pennica D, Shaw KJ, Swanson TA, et al. Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem 1995; 270(18): 10915–22

    Article  PubMed  CAS  Google Scholar 

  42. Pennica D, Wood WI, Chien KR. Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. Cytokine Growth Factor Rev 1996; 7(1): 81–91

    Article  PubMed  CAS  Google Scholar 

  43. Robledo O, Fourcin M, Chevalier S, et al. Signaling of the cardiotrophin-1 receptor. Evidence for a third receptor component. J Biol Chem 1997; 272(8): 4855–63

    Article  PubMed  CAS  Google Scholar 

  44. Kurek JB, Radford AJ, Crump DE, et al. LIF (AM424), a promising growth factor for the treatment of ALS. J Neurol Sci 1998; 160 Suppl. 1: S106–13

    Article  PubMed  CAS  Google Scholar 

  45. Blesch A, Uy HS, Grill RJ, et al. Leukemia inhibitory factor augments neurotrophin expression and corticospinal axon growth after adult CNS injury. J Neurosci 1999; 19(9): 3556–66

    PubMed  CAS  Google Scholar 

  46. Ebendal T, Bengtsson H, Soderstrom S. Bone morphogenetic proteins and their receptors: potential functions in the brain. J Neurosci Res 1998; 51(2): 139–46

    Article  PubMed  CAS  Google Scholar 

  47. Helm GA, Alden TD, Sheehan JP, et al. Bone morphogenetic proteins and bone morphogenetic protein gene therapy in neurological surgery: a review. Neurosurgery 2000; 46(5): 1213–22

    Article  PubMed  CAS  Google Scholar 

  48. Nishitoh H, Ichijo H, Kimura M, et al. Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J Biol Chem 1996; 271(35): 21345–52

    Article  PubMed  CAS  Google Scholar 

  49. Krieglstein K, Suter-Crazzolara C, Hotten G, et al. Trophic and protective effects of growth/differentiation factor 5, a member of the transforming growth factor-beta superfamily, on midbrain dopaminergic neurons. J Neurosci Res 1995; 42(5): 724–32

    Article  PubMed  CAS  Google Scholar 

  50. Sullivan AM, Opacka-Juffry J, Pohl J, et al. Neuroprotective effects of growth/differentiation factor 5 depend on the site of administration. Brain Res 1999; 818(1): 176–9

    Article  PubMed  CAS  Google Scholar 

  51. Strelau J, Sullivan A, Bottner M, et al. Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci 2000; 20(23): 8597–603

    PubMed  CAS  Google Scholar 

  52. Wang Y, Lin SZ, Chiou AL, et al. Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex. J Neurosci 1997; 17(11): 4341–8

    PubMed  CAS  Google Scholar 

  53. Watabe K, Ohashi T, Sakamoto T, et al. Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor. J Neurosci Res 2000; 60(4): 511–9

    Article  PubMed  CAS  Google Scholar 

  54. Perez-Navarro E, Akerud P, Marco S, et al. Neurturin protects striatal projection neurons but not interneurons in a rat model of Huntington’s disease. Neuroscience 2000; 98(1): 89–96

    Article  PubMed  CAS  Google Scholar 

  55. Milbrandt J, de Sauvage FJ, Fahrner TJ, et al. Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 1998; 20(2): 245–53

    Article  PubMed  CAS  Google Scholar 

  56. Masure S, Cik M, Hoefnagel E, et al. Mammalian a-4, a divergent member of the GFRa family of coreceptors for glial cell line-derived neurotrophic factor family ligands, is a receptor for the neurotrophic factor persephin. J Biol Chem 2000; 275(50): 39427–34

    Article  PubMed  CAS  Google Scholar 

  57. Kotzbauer PT, Lampe PA, Heuckeroth RO, et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 1996; 384(6608): 467–70

    Article  PubMed  CAS  Google Scholar 

  58. Golden JP, Baloh RH, Kotzbauer PT, et al. Expression of neurturin, GDNF, and their receptors in the adult mouse CNS. J Comp Neurol 1998; 398(1): 139–50

    Article  PubMed  CAS  Google Scholar 

  59. GFR(alpha) Nomenclature Committee. Nomenclature of GPI-linked receptors for the GDNF ligand family. GFR(alpha) Nomenclature Committee. Neuron 1997; 19(3): 485

    Google Scholar 

  60. Bilak MM, Shifrin DA, Corse AM, et al. Neuroprotective utility and neurotrophic action of neurturin in postnatal motor neurons: comparison with GDNF and persephin. Mol Cell Neurosci 1999; 13(5): 326–36

    Article  PubMed  CAS  Google Scholar 

  61. Baloh RH, Tansey MG, Lampe PA, et al. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron 1998; 21(6): 1291–302

    Article  PubMed  CAS  Google Scholar 

  62. Henrich-Noack P, Prehn JH, Krieglstein J. TGF-beta 1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose-response relationship and potential neuroprotective mechanisms. Stroke 1996; 27(9): 1609–14; discussion 15

    Article  PubMed  CAS  Google Scholar 

  63. Pratt BM, McPherson JM. TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. Cytokine Growth Factor Rev 1997; 8(4): 267–92

    Article  PubMed  CAS  Google Scholar 

  64. Adlkofer K, Lai C. Role of neuregulins in glial cell development. Glia 2000; 29(2): 104–11

    Article  PubMed  CAS  Google Scholar 

  65. Gozes I, Davidson A, Gozes Y, et al. Antiserum to activity-dependent neurotrophic factor produces neuronal cell death in CNS cultures: immunological and biological specificity. Brain Res Dev Brain Res 1997; 99(2): 167–75

    Article  PubMed  CAS  Google Scholar 

  66. Brenneman DE, Gozes I. A femtomolar-acting neuroprotective peptide. J Clin Invest 1996; 97(10): 2299–307

    Article  PubMed  CAS  Google Scholar 

  67. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999; 79(4): 1283–316

    PubMed  CAS  Google Scholar 

  68. Gotz R, Koster R, Winkler C, et al. Neurotrophin-6 is a new member of the nerve growth factor family. Nature 1994; 372(6503): 266–9

    Article  PubMed  CAS  Google Scholar 

  69. Nilsson AS, Fainzilber M, Falck P, et al. Neurotrophin-7: a novel member of the neurotrophin family from the zebrafish. FEBS Lett 1998; 424(3): 285–90

    Article  PubMed  CAS  Google Scholar 

  70. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319(6056): 743–8

    Article  PubMed  CAS  Google Scholar 

  71. Bothwell M. Keeping track of neurotrophin receptors. Cell 1991; 65(6): 915–8

    Article  PubMed  CAS  Google Scholar 

  72. Squinto SP, Stitt TN, Aldrich TH, et al. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell 1991; 65(5): 885–93

    Article  PubMed  CAS  Google Scholar 

  73. Knusel B, Michel PP, Schwaber JS, et al. Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J Neurosci 1990; 10(2): 558–70

    PubMed  CAS  Google Scholar 

  74. Knusel B, Winslow JW, Rosenthal A, et al. Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. Proc Natl Acad Sci U S A 1991; 88(3): 961–5

    Article  PubMed  CAS  Google Scholar 

  75. Nishimura T, Nakatake Y, Konishi M, et al. Identification of a novel FGF, FGF-21, preferentially expressed in liver. Biochim Biophys Acta 2000; 1492: 203–6

    Article  PubMed  CAS  Google Scholar 

  76. Masiakowski P, Liu H, Radziejewski C, et al. Recombinant human and rat ciliary neurotrophic factors. J Neurochem 1991; 57: 1003–12

    Article  PubMed  CAS  Google Scholar 

  77. Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol 1998; 16(3): 247–52

    Article  PubMed  CAS  Google Scholar 

  78. Massague J. TGFb signaling: receptors, transducers, and mad proteins. Cell 1996; 85: 947–50

    Article  PubMed  CAS  Google Scholar 

  79. Morrison R. Epidermal growth factor: structure, expression, and functions in the central nervous system. In: Loughlin SE, Fallon JH, editors. Neurotrophic factors. San Diego (CA): Academic Press, Inc., 1993: 339–57

    Google Scholar 

  80. Minghetti L, Goodearl AD, Mistry K, et al. Glial growth factors I–III are specific mitogens for glial cells. J Neurosci Res 1996; 43(6): 684–93

    Article  PubMed  CAS  Google Scholar 

  81. Mahanthappa NK, Anton ES, Matthew WD. Glial growth factor 2, a soluble neuregulin, directly increases Schwann cell motility and indirectly promotes neurite outgrowth. J Neurosci 1996; 16(15): 4673–83

    PubMed  CAS  Google Scholar 

  82. LeRoith D, Werner H, Faria TN, et al. CTR. Insulin-like growth factor receptors: implications for nervous system function. Ann N Y Acad Sci 1993; 692: 22–32

    Article  PubMed  CAS  Google Scholar 

  83. Adamo M, Raizada MK, LeRoith D. Insulin and insulin-like growth factor receptors in the nervous system. Mol Neurobiol 1989; 3: 71–100

    Article  PubMed  CAS  Google Scholar 

  84. Baxter RC, Binoux MA, Clemmons DR, et al. Recommendations for nomenclature of the insulin-like growth factor binding protein superfamily. J Clin Endocrinol Metab 1998; 83(9): 3213

    Article  PubMed  CAS  Google Scholar 

  85. Raines EW, Ross R. Platelet-derived growth factor. I. High yield purification and evidence for multiple forms. J Biol Chem 1982; 257(9): 5154–60

    PubMed  CAS  Google Scholar 

  86. Fretto LJ, Snape AJ, Tomlinson JE, et al. Mechanism of platelet-derived growth factor (PDGF) AA, AB, and BB binding to alpha and beta PDGF receptor. J Biol Chem 1993; 268(5): 3625–31

    PubMed  CAS  Google Scholar 

  87. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001; 291: 1304–51

    Article  PubMed  CAS  Google Scholar 

  88. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921

    Article  Google Scholar 

  89. Pandey A, Mann M. Proteomics to study genes and genomes. Nature 2000; 405(6788): 837–46

    Article  PubMed  CAS  Google Scholar 

  90. Desai MM, Zhang P, Hennessy CH. Surveillance for morbidity and mortality among older adults. United States, 1995–1996. Mor Mortal Wkly Rep CDC Surveill Summ 1999; 48(8): 7–25

    CAS  Google Scholar 

  91. Shoulson I. Experimental therapeutics of neurodegenerative disorders: unmet needs. Science 1998; 282: 1072–4

    Article  PubMed  CAS  Google Scholar 

  92. Hock C, Heese K, Hulette C, et al. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 2000; 57(6): 846–51

    Article  PubMed  CAS  Google Scholar 

  93. Hock C, Heese K, Muller-Spahn F, et al. Increased CSF levels of nerve growth factor in patients with Alzheimer’s disease. Neurology 2000; 54(10): 2009–11

    Article  PubMed  CAS  Google Scholar 

  94. Vawter MP, Dillon-Carter O, Tourtellotte WW, et al. TGFbeta2 concentrations are elevated in Parkinson’s disease in ventricular cerebrospinal fluid. Exp Neurol 1996; 142(2): 313–22

    Article  PubMed  CAS  Google Scholar 

  95. Capsoni S, Ugolini G, Comparini A, et al. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci U S A 2000; 97(12): 6826–31

    Article  PubMed  CAS  Google Scholar 

  96. Arakawa Y, Sendtner M, Thoenen H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci 1990; 10(11): 3507–15

    PubMed  CAS  Google Scholar 

  97. Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 1986; 6(8): 2155–62

    PubMed  CAS  Google Scholar 

  98. Sendtner M, Holtmann B, Kolbeck R, et al. Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 1992; 360(6406): 757–9

    Article  PubMed  CAS  Google Scholar 

  99. Gluckman P, Klempt N, Guan J, et al. A role for IGF-I in the rescue of CNS neurons following hypoxic ischemic injury. Biochem Biophys Res Commun 1992; 182(2): 593–9

    Article  PubMed  CAS  Google Scholar 

  100. Gross CC. Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 2000; 1: 67–73

    Article  PubMed  CAS  Google Scholar 

  101. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4(11): 1313–7

    Article  PubMed  CAS  Google Scholar 

  102. Wagner JP, Black IB, DiCicco-Bloom E. Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci 1999; 19(14): 6006–16

    PubMed  CAS  Google Scholar 

  103. Aberg MA, Aberg ND, Hedbacker H, et al. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 2000; 20(8): 2896–903

    PubMed  CAS  Google Scholar 

  104. Emilien G, Beyreuther K, Masters CL, et al. Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 2000; 57: 454–9

    Article  PubMed  CAS  Google Scholar 

  105. Giacobini E. Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 2000; 14 Suppl. 1: S3–10

    Article  PubMed  CAS  Google Scholar 

  106. Marx J. NGF and Alzheimer’s: hopes and fears. Science 1990; 247: 408–10

    Article  PubMed  CAS  Google Scholar 

  107. Koliatsos VE, Clatterbuck RE, Nauta HJ, et al. Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primates. Ann Neurol 1991; 30(6): 831–40

    Article  PubMed  CAS  Google Scholar 

  108. Davson H, Welch K, Segal MB. Physiology and pathophysiology of the cerebrospinal fluid. Edinburgh: Churchill Livingstone, 1987

    Google Scholar 

  109. Greitz D. Cerebrospinal fluid circulation and associated intracranial dynamics: a radiologic investigation using MR imaging and radionuclide cisternography. Acta Radiol 1993; 34 Suppl. 386: 1–23

    Google Scholar 

  110. Foldi M. The brain and the lymphatic system (I). Lymphology 1996; 29: 1–9

    PubMed  CAS  Google Scholar 

  111. Kida S, Pantazis A, Weiler RO. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 1993; 19: 480–8

    Article  PubMed  CAS  Google Scholar 

  112. Lowhagen P, Johansson BB, Nordborg C. The nasal route of cerebrospinal fluid drainage in man. A light-microscope study. Neuropathol Appl Neurobiol 1994; 20: 543–50

    Article  PubMed  CAS  Google Scholar 

  113. Frey WH, Liu J, Chen X, et al. Delivery of 125I-NGF to the brain via the olfactory route. Drug Deliv 1997; 4: 87–92

    Article  CAS  Google Scholar 

  114. Thorne RG, Emory CR, Ala TA, et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995; 692: 278–82

    Article  PubMed  CAS  Google Scholar 

  115. Kroin JS. Intrathecal drug administration. Present use and future trends. Clin Pharmacokinet 1992; 22(5): 319–26

    Article  PubMed  CAS  Google Scholar 

  116. Walsh G. Biopharmaceutical benchmarks. Nat Biotechnol 2000; 18: 831–3

    Article  PubMed  CAS  Google Scholar 

  117. McMartin C. Peptide and protein drugs. In: Welling PG, Balant LP, editors. Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1994: 371–82

    Google Scholar 

  118. Egleton RD, Davis TP. Bioavailability and transport of peptides and peptide drugs into the brain. Peptides 1997; 18(9): 1431–9

    Article  PubMed  CAS  Google Scholar 

  119. Braeckman R. Pharmacokinetics and pharmacodynamics of protein therapeutics. In: Reid RE, editor. Peptide and protein drug analysis. New York: Marcel Dekker, Inc., 2000: 633–69

    Google Scholar 

  120. Gillette JR. Overview of drug-protein binding. Ann N Y Acad Sci 1973; 226: 6–17

    Article  PubMed  CAS  Google Scholar 

  121. Taipale J, Keski-Oja J. Growth factors in the extracellular matrix. FASEB J 1997; 11(1): 51–9

    PubMed  CAS  Google Scholar 

  122. Øie S, Benet LZ. The effect of route of administration and distribution on drug action. In: Banker GS, Rhodes CT, editors. Modern pharmaceutics. 3rd ed. New York: Marcel Dekker, Inc., 1996: 155–78

    Google Scholar 

  123. Hunt CA, MacGregor RD, Siegel RA. Engineering targeted in vivo drug delivery: I. The physiological and physicochemical principles governing opportunities and limitations. Pharm Res 1986; 3: 333–44

    Article  CAS  Google Scholar 

  124. Rowland M, McLachlan A. Pharmacokinetic considerations of regional administration and drug targeting: influence of site of input in target tissue and flux of binding protein. J Pharmacokinet Biopharm 1996; 24(4): 369–87

    PubMed  CAS  Google Scholar 

  125. McDonald NQ, Chao MV. Structural determinants of neurotrophin action. J Biol Chem 1995; 270(34): 19669–72

    Article  PubMed  CAS  Google Scholar 

  126. Lewin GR, Barde YA. Physiology of the neurotrophins. Annu Rev Neurosci 1996; 19: 289–317

    Article  PubMed  CAS  Google Scholar 

  127. Perdue JF. Chemistry, structure, and function of insulin-like growth factors and their receptors: a review. Can J Biochem Cell Biol 1984; 62: 1237–45

    Article  PubMed  CAS  Google Scholar 

  128. Thomas KA. Biochemistry and molecular biology of fibroblast growth factors. In: Loughlin SE, Fallon JH, editors. Neurotrophic factors. San Diego (CA): Academic Press, Inc., 1993: 285–312

    Google Scholar 

  129. Savage CR, Inagami T, Cohen S. The primary structure of epidermal growth factor. J Biol Chem 1972; 247: 7612–21

    PubMed  CAS  Google Scholar 

  130. Pan W, Banks WA, Kastin AJ. Permeability of the blood-brain barrier to neurotrophins. Brain Res 1998; 788: 87–94

    Article  PubMed  CAS  Google Scholar 

  131. Barnett J, Chow J, Nguyen B, et al. Physicochemical characterization of recombinant human nerve growth factor produced in insect cells with a baculovirus vector. J Neurochem 1991; 57: 1052–61

    Article  PubMed  CAS  Google Scholar 

  132. Goldstein LD, Reynolds CP, Perez-Polo JR. Isolation of human nerve growth factor from placental tissue. Neurochem Res 1978; 3: 175–83

    Article  PubMed  CAS  Google Scholar 

  133. Rusenko KW, Stach RW Interaction of [125I]β nerve growth factor with acidic proteins. Neurochem Res 1981; 6(3): 287–300

    Article  PubMed  CAS  Google Scholar 

  134. Murase K, Takeuchi R, Iwata E, et al. Developmental changes in nerve growth factor level in rat serum. J Neurosci Res 1992; 33(2): 282–8

    Article  PubMed  CAS  Google Scholar 

  135. Liebl DJ, Koo PH. Comparative binding of neurotrophins (NT-3, CNTF and NGF) and various cytokines to alpha 2-macroglobulin. Biochem Biophys Res Commun 1993; 193(3): 1255–61

    Article  PubMed  CAS  Google Scholar 

  136. Nguyen CB, Szonyi E, Sadick MD, et al. Stability and interactions of recombinant human nerve growth factor in different biological matrices: in vitro and in vivo studies. Drug Metab Dispos 2000; 28(5): 590–7

    PubMed  CAS  Google Scholar 

  137. DiStefano PS, Johnson EMJ. Identification of a truncated form of the nerve growth factor receptor. Proc Natl Acad Sci U S A 1988; 85(1): 270–4

    Article  PubMed  CAS  Google Scholar 

  138. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 1978; 253(8): 2769–76

    PubMed  CAS  Google Scholar 

  139. Li CH, Yamashiro D, Gospodarowicz D, et al. Total synthesis of insulin-like growth factor I (somatomedin C). Proc Natl Acad Sci U S A 1983; 80: 2216–20

    Article  PubMed  CAS  Google Scholar 

  140. Frystyk J, Skjaerbaek C, Dinesen B, et al. Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Lett 1994; 348: 185–91

    Article  PubMed  CAS  Google Scholar 

  141. Spagnoli A, Rosenfeld RG. Insulinlike growth factor binding proteins. Curr Opin Endocrinol Diabetes 1997; 4: 1–9

    Article  CAS  Google Scholar 

  142. Scott CD, Ballesteros M, Madrid J, et al. Soluble insulin-like growth factor-II/mannose 6-P receptor inhibits deoxyribonucleic acid synthesis in cultured rat hepatocytes. Endocrinology 1996; 137(3): 873–8

    Article  PubMed  CAS  Google Scholar 

  143. Karey KP, Sirbasku DA. Glutaraldehyde fixation increases retention of low molecular weight proteins (growth factors) transferred to nylon membranes for western blot analysis. Anal Biochem 1989; 178: 255–9

    Article  PubMed  CAS  Google Scholar 

  144. Deguchi Y, Naito T, Yuge T, et al. Blood-brain barrier transport of 125I-labeled basic fibroblast growth factor. Pharm Res 2000; 17(1): 63–9

    Article  PubMed  CAS  Google Scholar 

  145. Dennis PA, Saksela O, Harpel P, et al. Alpha 2-macroglobulin is a binding protein for basic fibroblast growth factor. J Biol Chem 1989; 264(13): 7210–6

    PubMed  CAS  Google Scholar 

  146. Hanneken A, Ying W, Ling N, et al. Identification of soluble forms of the fibroblast growth factor receptor in blood. Proc Natl Acad Sci U S A 1994; 91(19): 9170–4

    Article  PubMed  CAS  Google Scholar 

  147. Antoniades HN, Scher CD, Stiles CD. Purification of human platelet-derived growth factor. Proc Natl Acad Sci U S A 1979; 76(4): 1809–13

    Article  PubMed  CAS  Google Scholar 

  148. Deuel TF, Huang JS, Proffitt RT, et al. Human platelet-derived growth factor. Purification and resolution into two active protein fractions. J Biol Chem 1981; 256(17): 8896–9

    PubMed  CAS  Google Scholar 

  149. Gonias SL, Carmichael A, Mettenburg JM, et al. Identical or overlapping sequences in the primary structure of human alpha(2)-macroglobulin are responsible for the binding of nerve growth factor-beta, platelet-derived growth factor-BB, and transforming growth factor-beta. J Biol Chem 2000; 275(8): 5826–31

    Article  PubMed  CAS  Google Scholar 

  150. Nexo E, Jorgensen PE, Hansen MR. Human epidermal growth factor-on molecular forms present in urine and blood. Regul Pept 1992; 42: 75–84

    Article  PubMed  CAS  Google Scholar 

  151. Pan W, Kastin A. Entry of EGF into brain is rapid and saturable. Peptides 1999; 20: 1091–8

    Article  PubMed  Google Scholar 

  152. Kim DC, Sugiyama Y, Fuwa T, et al. Kinetic analysis of the elimination process of human epidermal growth factor (hEGF) in rats. Biochem Pharmacol 1989; 38(2): 241–9

    Article  PubMed  CAS  Google Scholar 

  153. Nieto-Sampedro M, Broderick JT. A soluble brain molecule related to epidermal growth factor receptor is a mitogen inhibitor for astrocytes. J Neurosci Res 1989; 22(1): 28–35

    Article  PubMed  CAS  Google Scholar 

  154. Negro A, Corona G, Bigon E, et al. Synthesis, purification, and characterization of human ciliary neuronotrophic factor from E. coli. J Neurosci Res 1991; 29: 251–60

    Article  PubMed  CAS  Google Scholar 

  155. Marquardt H, Hunkapiller MW, Hood LE, et al. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 1984; 223: 1079–82

    Article  PubMed  CAS  Google Scholar 

  156. Kuo K-W, Yeh H-W, Chu DZJ, et al. Separation and microanalysis of growth factors by Phast system gel electrophoresis and by DNA synthesis in cell culture. J Chromatogr B Biomed Sci Appl 1991; 543: 463–70

    CAS  Google Scholar 

  157. Pan W, Vallance K, Kastin AJ. TGFa and the blood-brain barrier: accumulation in cerebral vasculature. Exp Neurol 1999; 160: 454–9

    Article  PubMed  CAS  Google Scholar 

  158. Malamud D, Drysdale JW. Isoelectric points of proteins: a table. Anal Biochem 1978; 86: 620–47

    Article  PubMed  CAS  Google Scholar 

  159. Shulz RM, Liebman MN. Proteins I: composition and structure. In: Devlin TM, editor. Textbook of biochemistry with clinical correlations. 3rd ed. New York: Wiley, 1992: 25–88

    Google Scholar 

  160. Banks WA, Kastin AJ. Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 1985; 15: 287–92

    Article  PubMed  CAS  Google Scholar 

  161. Rockich KT, Hatten JC, Kryscio RJ, et al. Effect of recombinant human growth hormone and insulin-like growth factor-1 administration on IGF-1 and IGF-binding protein-3 levels in brain injury. Pharmacotherapy 1999; 19(12): 1432–6

    Article  PubMed  CAS  Google Scholar 

  162. Kupfer SR, Underwood LE, Baxter RC, et al. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest 1993; 91(2): 391–6

    Article  PubMed  CAS  Google Scholar 

  163. Blomback B, Hanson LA, editors. Plasma proteins. Chichester: John Wiley & Sons, 1979

    Google Scholar 

  164. Calissano P, Cozzari C. Interaction of nerve growth factor with the mouse-brain neurotubule protein(s). Proc Natl Acad Sci U S A 1974; 71(5): 2131–5

    Article  PubMed  CAS  Google Scholar 

  165. Hoener MC, Varon S. Reversible sedimentation and masking of nerve growth factor (NGF) antigen by high molecular weight fractions from rat brain. Brain Res 1997; 772: 1–8

    Article  PubMed  CAS  Google Scholar 

  166. Koo PH, Stach RW Interaction of nerve growth factor with murine alpha-macroglobulin. J Neurosci Res 1989; 22(3): 247–61

    Article  PubMed  CAS  Google Scholar 

  167. Hintzen RQ, van Lier RA, Kuijpers KC, et al. Elevated levels of a soluble form of the T cell activation antigen CD27 in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 1991; 35(1-3): 211–7

    Article  PubMed  CAS  Google Scholar 

  168. Clemmons DR, Jones JI, Busby WH, et al. Role of insulin-like growth factor binding proteins in modifying IGF actions. Ann N Y Acad Sci 1993; 692: 10–21

    Article  PubMed  CAS  Google Scholar 

  169. Tanaka Y, Kitao K, Hata T, et al. Kidney as an important metabolic organ for recombinant human insulin-like growth factor-I. Res Commun Mol Pathol Pharmacol 1997; 96(3): 267–76

    PubMed  CAS  Google Scholar 

  170. Froesch ER, Zapf J. Insulin-like growth factors and insulin: comparative aspects. Diabetologia 1985; 28: 485–93

    Article  PubMed  CAS  Google Scholar 

  171. Frystyk J, Gronbaek H, Skjaerbaek C, et al. Effect of hyperthyroidism on circulating levels of free and total IGF-1 and IGFBPs in rats. Am J Physiol 1995; 269: E840–5

    PubMed  CAS  Google Scholar 

  172. Skjaerbaek C, Frystyk J, Grofte T, et al. Serum free insulin-like growth factor-I is dose-dependently decreased by methylprednisolone and related to body weight changes in rats. Growth Horm IGF Res 1999; 9: 74–80

    Article  PubMed  CAS  Google Scholar 

  173. Loddick SA, Liu X-J, Lu Z-X, et al. Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke. Proc Natl Acad Sci U S A 1998; 95: 1894–8

    Article  PubMed  CAS  Google Scholar 

  174. Ocrant I, Fay CT, Parmelee JT. Characterization of insulin-like growth factor binding proteins produced in the rat central nervous system. Endocrinology 1990; 127(3): 1260–7

    Article  PubMed  CAS  Google Scholar 

  175. LeRoith D, Roberts Jr CT, Werner H, Bondy C, et al. Insulin-like growth factors in the brain. In: Loughlin SE, Fallon JH, editors. Neurotrophic factors. San Diego (CA): Academic Press, Inc., 1993: 391–414

    Google Scholar 

  176. Clairmont KB, Czech MP. Extracellular release as the major degradative pathway of the insulin-like growth factor II/mannose 6-phosphate receptor. J Biol Chem 1991; 266(19): 12131–4

    PubMed  CAS  Google Scholar 

  177. Hanneken A, Frautschy S, Galasko D, et al. A fibroblast growth factor binding protein in human cerebral spinal fluid. Neuroreport 1995; 6(6): 886–8

    Article  PubMed  CAS  Google Scholar 

  178. Zaina S, Newton RV, Paul MR, et al. Local reduction of organ size in transgenic mice expressing a soluble insulin-like growth factor II/mannose-6-phosphate receptor. Endocrinology 1998; 139(9): 3886–95

    Article  PubMed  CAS  Google Scholar 

  179. Fung LK, Ewend MG, Sills A, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 1998; 58(4): 672–84

    PubMed  CAS  Google Scholar 

  180. Zoli M, Jansson A, Syková E, et al. Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci 1999; 20: 142–50

    Article  PubMed  CAS  Google Scholar 

  181. Rennels ML, Gregory TF, Blaumanis OR, et al. Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 1985; 326(1): 47–63

    Article  PubMed  CAS  Google Scholar 

  182. Nicholson C, Syková E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci 1998; 21(5): 207–15

    Article  PubMed  CAS  Google Scholar 

  183. Krewson CE, Klarman ML, Saltzman WM. Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res 1995; 680(1-2): 196–206

    Article  PubMed  CAS  Google Scholar 

  184. Muramatsu N, Minton AP. Tracer diffusion of globular proteins in concentrated protein solutions. Proc Natl Acad Sci U S A 1988; 85: 2984–8

    Article  PubMed  CAS  Google Scholar 

  185. O’Leary TJ. Concentration dependence of protein diffusion. Biophys J 1987; 52: 137–9

    Article  PubMed  Google Scholar 

  186. Fenstermacher J, Kaye T. Drug ‘diffusion’ within the brain. Ann N Y Acad Sci 1988; 531: 29–39

    Article  PubMed  CAS  Google Scholar 

  187. Tao L, Nicholson C. Diffusion of albumins in rat cortical slices and relevance to volume transmission. Neuroscience 1996; 75(3): 839–47

    Article  PubMed  CAS  Google Scholar 

  188. Nicholson C, Tao L. Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J 1993; 65(6): 2277–90

    Article  PubMed  CAS  Google Scholar 

  189. Busch NA, Kim T, Bloomfield VA. Tracer diffusion of proteins in DNA solutions. 2. Green fluorescent protein in crowded DNA solutions. Macromolecules 2000; 33: 5932–7

    Article  CAS  Google Scholar 

  190. Berg HC. Random walks in biology. Princeton (NJ): Princeton University Press, 1993

    Google Scholar 

  191. Saltzman WM, Mak MW, Mahoney MJ, et al. Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems. Pharm Res 1999; 16(2): 232–40

    Article  PubMed  CAS  Google Scholar 

  192. Haller MF, Saltzman WM. Localized delivery of proteins in the brain: can transport be customized? Pharm Res 1998; 15(3): 377–85

    Article  PubMed  CAS  Google Scholar 

  193. Ferguson IA, Schweitzer JB, Bartlett PF, et al. Receptor-mediated retrograde transport in CNS neurons after intraventricular administration of NGF and growth factors. J Comp Neurol 1991; 313(4): 680–92

    Article  PubMed  CAS  Google Scholar 

  194. Yan Q, Matheson C, Sun J, et al. Distribution of intracerebral ventricularly administered neurotrophins in rat brain and its correlation with Trk receptor expression. Exp Neurol 1994; 127: 23–36

    Article  PubMed  CAS  Google Scholar 

  195. Mufson EJ, Kroin JS, Liu Y-T, et al. Intrastriatal and intraventricular infusion of brain-derived neurotrophic factor in the cynomologous monkey: distribution, retrograde transport and co-localization with substantia nigra dopamine-containing neurons. Neuroscience 1996; 71(1): 179–91

    Article  PubMed  CAS  Google Scholar 

  196. Brightman MW. The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice. Prog Brain Res 1968; 29: 19–40

    Article  PubMed  CAS  Google Scholar 

  197. Hutchings M, Weller RO. Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 1986; 65(3): 316–25

    Article  PubMed  CAS  Google Scholar 

  198. Ichimura T, Fraser PA, Cserr HE Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res 1991; 545(1-2): 103–13

    Article  PubMed  CAS  Google Scholar 

  199. Guan J, Beilharz EJ, Skinner SJ, et al. Intracerebral transportation and cellular localisation of insulin-like growth factor-1 following central administration to rats with hypoxic-ischemic brain injury. Brain Res 2000; 853(2): 163–73

    Article  PubMed  CAS  Google Scholar 

  200. Guan J, Skinner SJ, Beilharz EJ, et al. The movement of IGF-I into the brain parenchyma after hypoxic-ischaemic injury. Neuroreport 1996; 7(2): 632–6

    Article  PubMed  CAS  Google Scholar 

  201. Olson L, Backlund EO, Ebendal T, et al. Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson’s disease. One-year follow-up of first clinical trial. Arch Neurol 1991; 48(4): 373–81

    Article  PubMed  CAS  Google Scholar 

  202. Olson L, Nordberg A, von Holst H, et al. Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J Neural Transm Park Dis Dement Sect 1992; 4(1): 79–95

    Article  PubMed  CAS  Google Scholar 

  203. Jönhagen ME, Nordberg A, Amberla K, et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 1998; 9: 246–57

    Article  Google Scholar 

  204. Petty BG, Cornblath DR, Adornate BT, et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994; 36: 244–6

    Article  PubMed  CAS  Google Scholar 

  205. Cedarbaum JM, Chapman C, Charatan M, et al. The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: relation to parameters of the acutephase response. The ALS CNTF Treatment Study (ACTS) Phase I–II Study Group. Clin Neuropharmacol 1995; 18(6): 500–14

    Article  CAS  Google Scholar 

  206. Aebischer P, Schluep M, Deglon N, et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med 1996; 2(6): 696–9

    Article  PubMed  CAS  Google Scholar 

  207. Penn RD, Kroin JS, York MM, et al. Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 1997; 40(1): 94–9

    PubMed  CAS  Google Scholar 

  208. Ochs G, Giess R, Bendszus M, et al. Epi-arachnoidal drug deposit: a rare complication of intrathecal drug therapy. J Pain Symptom Manage 1999; 18(3): 229–32

    Article  PubMed  CAS  Google Scholar 

  209. Broadwell RD. Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal. Acta Neuropathol (Berl) 1989; 79: 117–28

    Article  CAS  Google Scholar 

  210. Broadwell RD, Balin BJ, Salcman M. Transcytotic pathway for blood-borne protein through the blood-brain barrier. Proc Natl Acad Sci U S A 1988; 85: 632–6

    Article  PubMed  CAS  Google Scholar 

  211. Poduslo JF, Curran GL, Berg CT. Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc Natl Acad Sci U S A 1994; 91(12): 5705–9

    Article  PubMed  CAS  Google Scholar 

  212. Pan W, Banks WA, Fasold MB, et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998; 37(12): 1553–61

    Article  PubMed  CAS  Google Scholar 

  213. Friden PM, Walus LR, Watson P, et al. Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 1993; 259: 373–7

    Article  PubMed  CAS  Google Scholar 

  214. Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to the brain. Proc Natl Acad Sci U S A 1999; 96(1): 254–9

    Article  PubMed  CAS  Google Scholar 

  215. Jiao S, Miller PJ, Lapchak PA. Enhanced delivery of [125I]glial cell line-derived neurotrophic factor to the rat CNS following osmotic blood-brain barrier modification. Neurosci Lett 1996; 220(3): 187–90

    Article  PubMed  Google Scholar 

  216. Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999; 107 Suppl. 2B: S34–42

    Article  Google Scholar 

  217. Apfel SC, Kessler JA. Neurotrophic factors in the treatment of peripheral neuropathy. Ciba Found Symp 1996; 196: 98–108

    PubMed  CAS  Google Scholar 

  218. Hefti F, editor. Neurotrophic factors. Berlin: Springer-Verlag, 1999

    Google Scholar 

  219. Cedarbaum JM, Chapman C, Charatan M, et al. A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. The ALS CNTF Treatment Study (ACTS) Phase I–II Study Group. Clin Neuropharmacol 1995; 18(6): 515–32

    Article  CAS  Google Scholar 

  220. Cedarbaum JM, Chapman C, Charatan M, et al. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 1996; 46(5): 1244–9

    Article  Google Scholar 

  221. Boroujerdi MA, Sonksen PH, Jones RH. A compartmental model for simulation of IGF-I kinetics and metabolism. Methods Inf Med 1994; 33: 514–21

    PubMed  CAS  Google Scholar 

  222. Frystyk J, Hussain M, Skjaerbaek C, et al. The pharmacokinetics of free insulin-like growth factor-I in healthy subjects. Growth Horm IGF Res 1999; 9: 150–6

    Article  PubMed  CAS  Google Scholar 

  223. Skjaerbaek C, Frystyk J, Kaal A, et al. Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency. Clin Endocrinol (Oxf) 2000; 52: 25–33

    Article  CAS  Google Scholar 

  224. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology 1994; 135(5): 1753–61

    Article  PubMed  CAS  Google Scholar 

  225. Bondy CA, Lee W-H. Patterns of insulin-like growth factor and IGF receptor gene expression in the brain: functional implications. Ann N Y Acad Sci 1993; 692: 33–43

    Article  PubMed  CAS  Google Scholar 

  226. Pardridge WM. Transport of insulin-related peptides and glucose across the blood-brain barrier. Ann N Y Acad Sci 1993; 692: 126–37

    Article  PubMed  CAS  Google Scholar 

  227. Mackic JB, Weiss MH, Miao W, et al. Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer’s amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem 1998; 70(1): 210–5

    Article  PubMed  CAS  Google Scholar 

  228. Nitsch C, Goping G, Laursen H, et al. The blood-brain barrier to horseradish peroxidase at the onset of bicuculline-induced seizures in hypothalamus, pallidum, hippocampus, and other selected regions of the rabbit. Acta Neuropathol (Berl) 1986; 69(1-2): 1–16

    Article  CAS  Google Scholar 

  229. Plateel M, Teissier E, Cecchelli R. Hypoxia dramatically increases the nonspecific transport of blood-borne proteins to the brain. J Neurochem 1997; 68(2): 874–7

    Article  PubMed  CAS  Google Scholar 

  230. 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 (Berl) 1997; 94(2): 158–63

    Article  CAS  Google Scholar 

  231. Preston E, Foster DO. Evidence for pore-like opening of the blood-brain barrierfollowing forebrain ischemia in rats. Brain Res 1997; 761(1): 4–10

    Article  PubMed  CAS  Google Scholar 

  232. Tuomanen E. Entry of pathogens into the central nervous system. FEMS Microbiol Rev 1996; 18(4): 289–99

    Article  PubMed  CAS  Google Scholar 

  233. de Vries HE, Blom-Roosemalen MC, de Boer AG, et al. Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in vitro. J Pharmacol Exp Ther 1996; 277(3): 1418–23

    PubMed  Google Scholar 

  234. Moor AC, de Vries HE, de Boer AG, et al. The blood-brain barrier and multiple sclerosis. Biochem Pharmacol 1994; 47(10): 1717–24

    Article  PubMed  CAS  Google Scholar 

  235. Mahoney MJ, Saltzman WM. Millimeter-scale positioning of a nerve-growth-factor source and biological activity in the brain. Proc Natl Acad Sci U S A 1999; 96(8): 4536–9

    Article  PubMed  CAS  Google Scholar 

  236. Krewson CE, Saltzman WM. Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res 1996; 727(1-2): 169–81

    Article  PubMed  CAS  Google Scholar 

  237. Mahoney MJ, Saltzman WM. Controlled release of proteins to tissue transplants for the treatment of neurodegenerative disorders. J Pharm Sci 1996; 85(12): 1276–81

    Article  PubMed  CAS  Google Scholar 

  238. Krewson CE, Dause R, Mak M, et al. Stabilization of nerve growth factor in controlled release polymers and in tissue. J Biomater Sci Polym Ed 1996; 8(2): 103–17

    Article  PubMed  CAS  Google Scholar 

  239. Morse JK, Wiegand SJ, Anderson K, et al. Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection. J Neurosci 1993; 13(10): 4146–56

    PubMed  CAS  Google Scholar 

  240. Venero JL, Hefti F, Knusel B. Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration. Mol Pharmacol 1996; 49(2): 303–10

    PubMed  CAS  Google Scholar 

  241. Lapchak PA, Araujo DM, Carswell S, et al. Distribution of [125I]nerve growth factor in the rat brain following a single intraventricular injection: correlation with the topographical distribution of trkA messenger RNA-expressing cells. Neuroscience 1993; 54(2): 445–60

    Article  PubMed  CAS  Google Scholar 

  242. Emmett CJ, Stewart GR, Johnson RM, et al. Distribution of radioiodinated recombinant human nerve growth factor in primate brain following intracerebroventricular infusion. Exp Neurol 1996; 140: 151–60

    Article  PubMed  CAS  Google Scholar 

  243. Jonhagen ME. Nerve growth factor treatment in dementia. Alzheimer Dis Assoc Disord 2000; 14 Suppl. 1: S31–8

    Article  PubMed  CAS  Google Scholar 

  244. Kordower JH, Palfi S, Chen E-Y, et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 1999; 46(3): 419–24

    Article  PubMed  CAS  Google Scholar 

  245. Hao J, Ebendal T, Xu X, et al. Intracerebroventricular infusion of nerve growth factor induces pain-like response in rats. Neurosci Lett 2000; 286(3): 208–12

    Article  PubMed  CAS  Google Scholar 

  246. Johanson CE, Szmydynger-Chodobska J, Chodobski A, et al. Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus. Am J Physiol 1999; 277 (1 Pt 2): R263–71

    PubMed  CAS  Google Scholar 

  247. Dittrich F, Ochs G, Grobe-Wilde A, et al. Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons. Exp Neurol 1996; 141: 225–39

    Article  PubMed  CAS  Google Scholar 

  248. Gold BG. Axonal regeneration of sensory nerves is delayed by continuous intrathecal infusion of nerve growth factor. Neuroscience 1997; 76(4): 1153–8

    Article  PubMed  CAS  Google Scholar 

  249. Frey WH, Liu J, Thome RG, et al. Intranasal delivery of 125I-labeled nerve growth factor to the brain via the olfactory route. In: Iqbal K, Mortimer JA, Winblad B, et al., editors. Research advances in Alzheimer’s disease and related disorders. Chichester: John Wiley & Sons Ltd, 1995: 329–35

    Google Scholar 

  250. Ilium L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000; 11: 1–18

    Article  Google Scholar 

  251. Mathison S, Nagilla R, Kompella UB. Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target 1998; 5: 415–41

    Article  PubMed  CAS  Google Scholar 

  252. Baker H, Spencer RF. Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res 1986; 63(3): 461–73

    Article  PubMed  CAS  Google Scholar 

  253. Broadwell RD, Balin BJ. Endocytic and exocytic pathways of the neuronal secretory process and trans-synaptic transfer of wheat germ agglutinin-horseradish peroxidase in vivo. J Comp Neurol 1985; 242: 632–50

    Article  PubMed  CAS  Google Scholar 

  254. Shipley MT. Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium. Brain Res Bull 1985; 15(2): 129–42

    Article  PubMed  CAS  Google Scholar 

  255. Fawcett JR, Chen X, Rahman YE, et al. Previously reported nerve growth factor levels are underestimated due to an incomplete release from receptors and interaction with standard curve media. Brain Res 1999; 842(1): 206–10

    Article  PubMed  CAS  Google Scholar 

  256. Chen X-Q, Fawcett JR, Rahman Y-E, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimer Dis 1998; 1: 35–44

    CAS  Google Scholar 

  257. Gozes I, Bardea A, Reshef A, et al. Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide. Proc Natl Acad Sci U S A 1996; 93: 427–32

    Article  PubMed  CAS  Google Scholar 

  258. Gozes I, Giladi E, Pinhasov A, et al. Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a water maze. J Pharmacol Exp Ther 2000; 293(3): 1091–8

    PubMed  CAS  Google Scholar 

  259. Kucheryanu VG, Kryzhanovsky GN, Kudrin VS, et al. Intranasal fibroblast growth factors: delivery into the brain exerts antiparkinsonian effect in mice. In: Torchilin V, Veronese FM, editors. Proceedings of the 26th International Symposium on Controlled Release of Bioactive Materials; 1999 Jun 20–23; Boston. Deerfield (IL): Controlled Release Society, Inc., 1999: 643–4

    Google Scholar 

  260. Date I, Notter MF, Feiten SY, et al. MPTP-treated young mice but not aging mice show partial recovery of the nigrostriatal dopaminergic system by stereotaxic injection of acidic fibroblast growth factor (aFGF). Brain Res 1990; 526(1): 156–60

    Article  PubMed  CAS  Google Scholar 

  261. Date I, Yoshimoto Y, Imaoka T, et al. Enhanced recovery of the nigrostriatal dopaminergic system in MPTP-treated mice following intrastriatal injection of basic fibroblast growth factor in relation to aging. Brain Res 1993; 621(1): 150–4

    Article  PubMed  CAS  Google Scholar 

  262. Dahlin M, Bergman U, Jansson B, et al. Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000; 17(6): 737–42

    Article  PubMed  CAS  Google Scholar 

  263. Chen X. Investigation of delivery of nerve growth factor (NGF) to the central nervous system (CNS) via the olfactory neural pathway [PhD thesis]. Minneapolis (MN): University of Minnesota, 2000

    Google Scholar 

  264. DeSesso JM. The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways. Qual Assur 1993; 2(3): 213–31

    PubMed  CAS  Google Scholar 

  265. Roberts E. Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates. Neurobiol Aging 1986; 7: 561–7

    Article  PubMed  CAS  Google Scholar 

  266. Okuyama S. The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier. Life Sci 1997; 60(21): 1881–4

    Article  PubMed  CAS  Google Scholar 

  267. Riekkinen P, Legros J-J, Sennef C, et al. Penetration of DGAVP (Org 5667) across the blood-brain barrier in human subjects. Peptides 1987; 8: 261–5

    Article  PubMed  CAS  Google Scholar 

  268. Kern W, Born J, Schreiber H, et al. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 1999; 48: 557–63

    Article  PubMed  CAS  Google Scholar 

  269. Kern W, Schiefer B, Schwarzenburg J, et al. Evidence for central nervous effects of corticotropin-releasing hormone on gastric acid secretion in humans. Clin Neuroendocrinol 1997; 65: 291–8

    Article  CAS  Google Scholar 

  270. Perras B, Marshall L, Kohler G, et al. Sleep and endocrine changes after intranasal administration of growth hormone-releasing hormone in young and aged humans. Psychoneuro-endocrinology 1999; 24: 743–57

    Article  CAS  Google Scholar 

  271. Pietrowsky R, Struben C, Molle M, et al. Brain potential changes after intranasal vs. intravenous administration of vasopressin: evidence for a direct nose-brain pathway for peptide effects in humans. Biol Psychiatry 1996; 39: 332–40

    Article  PubMed  CAS  Google Scholar 

  272. Pietrowsky R, Thiemann A, Kern W, et al. A nose-brain pathway for psychotropic peptides: evidence from a brain evoked potential study with cholecystokinin. Psychoneuroendocrinology 1996; 21(6): 559–72

    Article  PubMed  CAS  Google Scholar 

  273. Fehm-Wolfsdorf G, Born J. Behavioral effects of neurohypophyseal peptides in healthy volunteers: 10 years of research. Peptides 1991; 12: 1399–406

    Article  PubMed  CAS  Google Scholar 

  274. Sakane T, Akizuki M, Yamashita S, et al. Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the dissociation of the drug. J Pharm Pharmacol 1994; 46: 378–9

    Article  PubMed  CAS  Google Scholar 

  275. Sakane T, Akizuki M, Yamashita S, et al. The transport of a drug to the cerebrospinal fluid from the nasal cavity: the relation to the lipophilicity of the drug. Chem Pharm Bull (Tokyo) 1991; 39(9): 2456–8

    Article  CAS  Google Scholar 

  276. Sakane T, Akizuki M, Taki Y, et al. Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the molecular weight of drugs. J Pharm Pharmacol 1995; 47: 379–81

    Article  PubMed  CAS  Google Scholar 

  277. Hussain AA. Intranasal drug delivery. Adv Drug Deliv Rev 1998; 29: 39–49

    Article  PubMed  CAS  Google Scholar 

  278. Washington N, McGlashan JA, Jackson SJ, et al. The effect of nasal patency on the clearance of radiolabeled saline in healthy volunteers. Pharm Res 2000; 17(6): 733–6

    Article  PubMed  CAS  Google Scholar 

  279. Bojsen-Moller F, Fahrenkrug J. Nasal swell bodies and cyclic changes in the air passage of the rat and rabbit nose. J Anat 1971; 110(1): 25–37

    PubMed  CAS  Google Scholar 

  280. Lowman HB, Chen YM, Skelton NJ, et al. Molecular mimics of insulin-like growth factor 1 (IGF-1) for inhibiting IGF-1: IGF-binding protein interactions. Biochemistry 1998; 37(25): 8870–8

    Article  PubMed  CAS  Google Scholar 

  281. Beglova N, LeSauteur L, Ekiel I, et al. Solution structure and internal motion of a bioactive peptide derived from nerve growth factor. J Biol Chem 1998; 273(37): 23652–8

    Article  PubMed  CAS  Google Scholar 

  282. Kaechi K, Furukawa Y, Ikegami R, et al. Pharmacological induction of physiologically active nerve growth factor in rat peripheral nervous system. J Pharmacol Exp Ther 1993; 264(1): 321–6

    PubMed  CAS  Google Scholar 

  283. Yamada K, Nitta A, Hasegawa T, et al. Orally active NGF synthesis stimulators: potential therapeutic agents in Alzheimer’s disease. Behav Brain Res 1997; 83(1-2): 117–22

    Article  PubMed  CAS  Google Scholar 

  284. Nitta A, Ogihara Y, Onishi J, et al. Propentofylline prevents neuronal dysfunction induced by infusion of anti-nerve growth factor antibody into the rat septum. Eur J Pharmacol 1996; 307(1): 1–6

    Article  PubMed  CAS  Google Scholar 

  285. Middlemiss PJ, Glasky AJ, Rathbone MP, et al. AIT-082, a unique purine derivative, enhances nerve growth factor mediated neurite outgrowth from PC12 cells. Neurosci Lett 1995; 199(2): 131–4

    Article  PubMed  CAS  Google Scholar 

  286. Rathbone MP, Middlemiss PJ, Gysbers JW, et al. Trophic effects of purines in neurons and glial cells. Prog Neurobiol 1999; 59(6): 663–90

    Article  PubMed  CAS  Google Scholar 

  287. Tirassa P, Aloe L, Stenfors C, et al. Cholecystokinin-8 protects central cholinergic neurons against fimbria-fornix lesion through the up-regulation of nerve growth factor synthesis. Proc Natl Acad Sci U S A 1999; 96(11): 6473–7

    Article  PubMed  CAS  Google Scholar 

  288. Snyder SH, Sabatini DM, Lai MM, et al. Neural actions of immunophilin ligands. Trends Pharmacol Sci 1998; 19(1): 21–6

    Article  PubMed  CAS  Google Scholar 

  289. Steiner JP, Hamilton GS, Ross DT, et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci U S A 1997; 94(5): 2019–24

    Article  PubMed  CAS  Google Scholar 

  290. Costantini LC, Isacson O. Immunophilin ligands and GDNF enhance neurite branching or elongation from developing dopamine neurons in culture. Exp Neurol 2000; 164(1): 60–70

    Article  PubMed  CAS  Google Scholar 

  291. Sharkey J, Butcher SP. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischemia. Nature 1994; 371: 336–9

    Article  PubMed  CAS  Google Scholar 

  292. Poduslo JF, Curran GL, Gill JS. Putrescine-modified nerve growth factor: bioactivity, plasma pharmacokinetics, blood-brain/nerve barrier permeability, and nervous system biodistribution. J Neurochem 1998; 71(4): 1651–60

    Article  PubMed  CAS  Google Scholar 

  293. Martinez-Serrano A, Bjorklund A. Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging. Proc Natl Acad Sci U S A 1998; 95(4): 1858–63

    Article  PubMed  CAS  Google Scholar 

  294. Smith DE, Roberts J, Gage FH, et al. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc Natl Acad Sci U S A 1999; 96(19): 10893–8

    Article  PubMed  CAS  Google Scholar 

  295. Tuszynski MH, Roberts J, Senut MC, et al. Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther 1996; 3(4): 305–14

    PubMed  CAS  Google Scholar 

  296. Mulligan RC. The basic science of gene therapy. Science 1993; 260: 926–32

    Article  PubMed  CAS  Google Scholar 

  297. Verma IM, Somia N. Gene therapy: promises, problems and prospects. Nature 1997; 389: 239–42

    Article  PubMed  CAS  Google Scholar 

  298. Bachoud-Levi AC, Deglon N, Nguyen JP, et al. Neuroprotective gene therapy for Huntington’s disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum Gene Ther 2000; 11(12): 1723–9

    Article  PubMed  CAS  Google Scholar 

  299. Meuli-Simmen C, Liu Y, Yeo TT, et al. Gene expression along the cerebral-spinal axis after regional gene delivery. Hum Gene Ther 1999; 10: 2689–700

    Article  PubMed  CAS  Google Scholar 

  300. Zhou LL, Huang L, Hayes RL, et al. Liposome-mediated NGF gene transfection following neuronal injury: Potential therapeutic applications. Gene Ther 1999; 6: 994–1005

    Article  CAS  Google Scholar 

  301. Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 2000; 290: 767–73

    Article  PubMed  CAS  Google Scholar 

  302. Mandir AS, Dawson VL, Dawson TM. Gene therapy to the rescue in Parkinson’s disease. Trends Pharmacol Sci 2001; 22: 103–5

    Article  PubMed  CAS  Google Scholar 

  303. Olson L. Combating Parkinson’s disease — step three. Science 2000; 290(5492): 721–4

    Article  PubMed  CAS  Google Scholar 

  304. Kafri T. Lentiviral vectors: regulated gene expression. Mol Ther 2000; 1: 516–21

    Article  PubMed  CAS  Google Scholar 

  305. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344: 710–9

    Article  PubMed  CAS  Google Scholar 

  306. Hottinger AF, Aebischer P. Strategies for administering neurotrophic factors to the central nervous system. In: Hefti F, editor. Neurotrophic factors. Berlin: Springer-Verlag, 1999: 255–80

    Chapter  Google Scholar 

  307. Zlokovic BV, Apuzzo ML. Cellular and molecular neurosurgery: pathways from concept to reality: part II. Vector systems and delivery methodologies for gene therapy of the central nervous system. Neurosurgery 1997; 40(4): 805–12

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Drs Aparna Lakkaraju, Tinna M. Laughlin and Cheryl L. Zinnerman for thoughtful discussions and manuscript review.

The authors wish to disclose their listing as inventors on patents and patent applications related to intranasal drug delivery. Dr Frey also serves as a consultant to Chiron Corporation.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thorne, R.G., Frey, W.H. Delivery of Neurotrophic Factors to the Central Nervous System. Clin Pharmacokinet 40, 907–946 (2001). https://doi.org/10.2165/00003088-200140120-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200140120-00003

Keywords

Navigation