Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. TargeT cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer s disease, Parkinson s disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.


Nerve Growth Factor Experimental Autoimmune Encephalomyelitis Cholinergic Neuron Basal Forebrain Neurotrophin Receptor 
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  1. 1.
    Gage FH. Mammalian neural stem cells. SCIENCE 2000; 287:1433–1438.PubMedCrossRefGoogle Scholar
  2. 2.
    Barde Y-A. The Nerve Growth Factor Family. Prog Growth Factor Res 1990; 2:237–348.PubMedCrossRefGoogle Scholar
  3. 3.
    Bibel M, Barde Y-A. Neurotrophins: Key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000; 14:2919–2937.PubMedCrossRefGoogle Scholar
  4. 4.
    Thoenen H. Treatment of degenerative disorders of the nervous system: From helpless descriptive categorization to rational therapeutic approaches. In: Ingoglia NA, Murray N, eds. Axonal Regeneration in the Central Nervous System. New York: Dekker M, 2001:675–697Google Scholar
  5. 5.
    Goyal L. Cell death inhibition: keeping caspases in check. Cell 2001; 104:805–808.PubMedCrossRefGoogle Scholar
  6. 6.
    McDonald NQ, Lapatto R, Murray-Rust J et al. New protein fold revealed by a 2.3-resolution crystal structure of nerve growth factor. Nature 1991; 354:411–414.PubMedCrossRefGoogle Scholar
  7. 7.
    McDonald NQ, Chao MV. Structural determinants of neurotrophin action. J Biol Chem 1995; 270:19669–19672.PubMedCrossRefGoogle Scholar
  8. 8.
    Lewin GR, Barde YA. Physiology of the Neurotrophins. Ann Rev Neurosci 1996; 19:289–317.PubMedCrossRefGoogle Scholar
  9. 9.
    Tria MA, Fusco M, Vantini G et al. Pharmacokinetics of nerve growth factor (NGF) following different routes of administration to adult rats. Exp Neurol 1994; 127:178–183.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Dittrich F, Ochs G, Grosse-Wilde A et al. Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons. Exp Neurol 1996; 141:225–239.PubMedCrossRefGoogle Scholar
  12. 12.
    Radziejewski C, Robinson RC. Heterodimers of the neurotrophic factors: Formation, isolation, and differential stability. Biochemistry 1993; 32:13350–13356.PubMedCrossRefGoogle Scholar
  13. 13.
    Arakawa T, Haniu M, Narhi LO et al. Formation of heterodimers from three neurotrophins, nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor. J Biol Chem 1994; 269:27833–27839.PubMedGoogle Scholar
  14. 14.
    Thoenen H. Neurotrophins and activity-dependent plasticity. Prog Brain Res 2000; 128:183–191.PubMedCrossRefGoogle Scholar
  15. 15.
    Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol 1994; 25:1386–1403.PubMedCrossRefGoogle Scholar
  16. 16.
    Grell M, Clauss M. TNF and TNF receptor superfamily. In: Bona CA, Revillard J-P, eds. Cytokines and Cytokine Receptors. New York: Harwood Academic Press, 2000:118–148.Google Scholar
  17. 17.
    Dechant G. Molecular interactions between neurotrophin receptors. Cell Tissue Res 2001; (online version Scholar
  18. 18.
    Dechant G, Rodr guez-T bar A, Barde Y-A. Neurotrophin Receptors. Prog Neurobiol 1994; 42:347–352.PubMedCrossRefGoogle Scholar
  19. 19.
    Davies AM. Neurotrophins: The yin and yang of nerve growth factor. Curr Biol 1997; 7:R38–R40.PubMedCrossRefGoogle Scholar
  20. 20.
    Snider WD. Functions of the neurotrophins during nervous system development: What the knockouts are teaching us. Cell 1994; 77:627–638.PubMedCrossRefGoogle Scholar
  21. 21.
    Holtzman DM, Li Y, Parada LF et al. p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF. Neuron 1992; 9:465–478.PubMedCrossRefGoogle Scholar
  22. 22.
    Hefti F. Nerve growth factor promotes survival of septal cholinergie neurons after fimbrial transections. J Neurosci 1986; 6:2155–2162.PubMedGoogle Scholar
  23. 23.
    Klein R, Martin-Zanca D, Barbacid M et al. Expression of the tyrosine kinase receptor gene TrkB is confined to the murine embryonic and adult nervous system. Development 1990; 109:845–850.PubMedGoogle Scholar
  24. 24.
    Klein R, Conway D, Parada LF et al. The TrkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 1990; 61:647–656.PubMedCrossRefGoogle Scholar
  25. 25.
    Middlemas DS, Lindberg RA, Hunter T. trk B, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 1991; 11:143–153.PubMedGoogle Scholar
  26. 26.
    Tessarollo L, TsoulFas P, Martin-Zanca D et al. TrkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development 1993; 118:463–475.PubMedGoogle Scholar
  27. 27.
    Barker PA. p75NTR: A study in contrasts [see comments]. Cell Death Differ 1998; 5:346–356.PubMedCrossRefGoogle Scholar
  28. 28.
    Dobrowsky RT, Carter BD. p75 neurotrophin receptor signaling: Mechanisms for neurotrophic modulation of cell stress J Neurosci Res 2000; 61:237–243.PubMedCrossRefGoogle Scholar
  29. 29.
    Frade JM, Barde YA. Nerve growth factor: Two receptors, multiple functions. BioEssays 1998; 20:137–145.PubMedCrossRefGoogle Scholar
  30. 30.
    Yamashita T, Tucker KL, Barde YA. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 1999; 24:585–593.PubMedCrossRefGoogle Scholar
  31. 31.
    Bibel M, Hoppe E, Barde YA. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J 1998; 616–622.Google Scholar
  32. 32.
    Majdan M, Miller FD. Neuronal life and death decisions functional antagonism between the Trk and p75 neurotrophin receptors. Int J Dev Neurosci 1999; 17:153–161.PubMedCrossRefGoogle Scholar
  33. 33.
    Vejsada R, Sagot Y, Kato AC. BDNF-mediated rescue of axotomized motor neurones decreases with increasing dose. NeuroReport 1994; 5:1889–1892.PubMedCrossRefGoogle Scholar
  34. 34.
    Vejsada R, Sagot Y, Kato AC. Quantitative comparison of the transient rescue effects of neurotrophic factors on axotomized motoneurons in vivo. Eur J Neurosci 1995; 7:108–115.PubMedCrossRefGoogle Scholar
  35. 35.
    Sommerfeld MT, Schweigreiter R, Barde YA et al. Down-regulation of the neurotrophin receptor TrkB following ligand binding. Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB. J Biol Chem 2000; 275:8982–8990.PubMedCrossRefGoogle Scholar
  36. 36.
    Carter BD, Zirrgiebel U, Barde Y-A. Differential regulation of p2l’ activation in neurons by nerve growth factor and brain-derived neurotrophic factor. J Biol Chem 1995; 270:21751–21757.PubMedCrossRefGoogle Scholar
  37. 37.
    Frank L, Ventimiglia R, Anderson K et al. BDNF down-regulates neurotrophin responsiveness, TrkB protein and TrkB mRNA levels in cultured rat hippocampal neurons. Eur J Neurosci 1996; 8:1220–1230.PubMedCrossRefGoogle Scholar
  38. 38.
    Widmer HR, Ohsawa F, Knusel B et al. Down-regulation of phosphatidylinositol response to BDNF and NT-3 in cultures of cortical neurons. Brain Res 1993; 614:325–334.PubMedCrossRefGoogle Scholar
  39. 39.
    Knusel B, Kaplan DR, Hefti F. Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation. Exp Neurol 1996; 139:121–130.PubMedCrossRefGoogle Scholar
  40. 40.
    Biffo S, Offenh user N, Carter BD et al. Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 1995; 121:2461–2470.PubMedGoogle Scholar
  41. 41.
    Von Bartheld CS, Kinoshita Y, Prevette D et al. Positive and negative effects of neurotrophins on the isthmo-optic nucleus in chick embryos. Neuron 1994; 12:639–654.PubMedCrossRefGoogle Scholar
  42. 42.
    Wiese S, Metzger F, Hohmann B et al. The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons. Eur J Neurosci 1999; 11:1668–1676.PubMedCrossRefGoogle Scholar
  43. 43.
    Klocker N, Cellerino A, Bahr M. Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells In vivo. J Neurosci 1998; 18:1038–1046.PubMedGoogle Scholar
  44. 44.
    Davies AM, Minichiello L, Klein R. Developmental changes in NT3 signalling via TrkA and TrkB in embryonic neurons. EMBO J 1995; 14:4482–4489.PubMedGoogle Scholar
  45. 45.
    Wyatt S, Pi n LGP, Ernfors P et al. Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos. EMBO J 1997; 16:3115–3123.PubMedCrossRefGoogle Scholar
  46. 46.
    Friedman WJ, Greene LA. Neurotrophin signaling via Trks and p75. Exp Cell Res 1999; 253:131–142.PubMedCrossRefGoogle Scholar
  47. 47.
    Yuen EC, Mobley WC. Early BDNF, NT-3, and NT-4 signaling events. Exp Neurol 1999; 159:297–308.CrossRefGoogle Scholar
  48. 48.
    Cunningham ME, Greene LA. A function-structure model for NGF-activated TRK. EMBO Journal 1998; 17:7282–7293.PubMedCrossRefGoogle Scholar
  49. 49.
    Kaplan DR, Miller FD. Signal transduction by the neurotrophin receptors. Curr Op Cell Biol 1997; 9:213–221.PubMedCrossRefGoogle Scholar
  50. 50.
    Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 13:2905–2927.PubMedCrossRefGoogle Scholar
  51. 51.
    Holgado-Madruga M, Moscatello DK, Emlet DR et al. Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. Proc Natl Acad Sci USA 1997; 94:12419–12424.PubMedCrossRefGoogle Scholar
  52. 52.
    Yamada M, Ohnishi H, Sano S et al. Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosinephosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. J Biol Chem 1997; 272:30334–30339.PubMedCrossRefGoogle Scholar
  53. 53.
    Canossa M, Gartner A, Campana G et al. Regulated secretion of neurotrophins by metabotropic glutamate group I (mG1uRI) and Trk receptor activation is mediated via phospholipase C signalling pathways. EMBO J 2001; 20:1640–1650.PubMedCrossRefGoogle Scholar
  54. 54.
    Maderdrut JL, Oppenheim RW, Prevette D. Enhancement of naturally occurring cell death in the sympathetic and parasympathetic ganglia of the chicken embryo following blockade of ganglionic transmission. Brain Res 1988; 444:189–194.PubMedCrossRefGoogle Scholar
  55. 55.
    Ghosh A, Carnahan J, Greenberg ME. Requirement for BDNF in activity-dependent survival of cortical neurons, SCIENCE 1994; 263:1618–1623.PubMedCrossRefGoogle Scholar
  56. 56.
    McAllister AK, Katz LC, Lo DC. Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 1996; 17:1057–1064.PubMedCrossRefGoogle Scholar
  57. 57.
    Brodski C, Schn rch H, Dechant G. Neurotrophin-3 promotes the cholinergie differentiation of sympathetic neurons. Proc Natl Acad of Sci USA 2000; 97:9683–9688.CrossRefGoogle Scholar
  58. 58.
    Dobrowsky RT, Jenkins GM, Hannun YA. Neurotrophins induce sphingomyelin hydrolysis Modulation by Co-expression of p751112.e with Trk receptors. J Biol Chem 1995; 270:22135–22142.PubMedCrossRefGoogle Scholar
  59. 59.
    Dobrowsky RT, Carter BD. Coupling of the p75 neurotrophin receptor to sphingolipid signaling. Ann NY Acad Sci 1998; 845:32–45.PubMedCrossRefGoogle Scholar
  60. 60.
    Carter BD, Kaltschmidt C, Kaltschmidt B et al. Selective activation of NF-kappaB by nerve growth factor through the neurotrophin receptor p75. Science 1996; 272:542–545.PubMedCrossRefGoogle Scholar
  61. 61.
    Hamanoue M, Middleton G, Wyatt S et al. p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol Cell Neurosci 1999; 14:28–40.PubMedCrossRefGoogle Scholar
  62. 62.
    Goldhawk DE, Meakin SO, Verdi JM. Subpopulations of rat B2’ neuroblasts exhibit differential neurotrophin responsiveness during sympathetic development. Dev Biol 2000; 218:367–377.PubMedCrossRefGoogle Scholar
  63. 63.
    Casaccia-Bonnefil P, Carter BD, Dobrowsky RT et al. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996; 383:716–719.PubMedCrossRefGoogle Scholar
  64. 64.
    Frade JM, Rodr guez-T bar A, Barde YA. Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 1996; 383:166–168.PubMedCrossRefGoogle Scholar
  65. 65.
    Agerman K, Baudet C, Fundin B et al. Attenuation of a caspase-3 dependent cell death in NT4- and p75-deficient embryonic sensory neurons. Mol Cell Neurosci 2000; 16:258–268.PubMedCrossRefGoogle Scholar
  66. 66.
    Yoon SO, Casaccia-Bonnefil P, Carter B et al. Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J Neurosci 1998; 18:3273–3281.PubMedGoogle Scholar
  67. 67.
    Aloyz RS, Bamji SX, Pozniak CD et al. P53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J Cell Biol 1998; 143:1691–1703.PubMedCrossRefGoogle Scholar
  68. 68.
    Pozniak CD, Radinovic S, Yang A et al. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. SCIENCE 2000; 289:304–306.PubMedCrossRefGoogle Scholar
  69. 69.
    Budd SL, Nicholls DG. Mitochondria in the life and death of neurons. Essays Biochem 1998; 33:43–52.PubMedGoogle Scholar
  70. 70.
    Martin Li. Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med 2001; 7:455–478.PubMedGoogle Scholar
  71. 71.
    Dugan LL, Creedon DJ, Johnson EM, Jr. et al. Rapid suppression of free radical formation by nerve growth factor involves the mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 1997; 94:4086–4091.PubMedCrossRefGoogle Scholar
  72. 72.
    Koh JY, Gwag BJ, Lobner D et al. Potentiated necrosis of cultured cortical neurons by neurotrophins. Science 1995; 268:573–575.PubMedCrossRefGoogle Scholar
  73. 73.
    Davies AM. The Bcl-2 family of proteins, and the regulation of neuronal survival. Trends Neurosci 1995; 18:355–358.PubMedCrossRefGoogle Scholar
  74. 74.
    Martin Li. Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 1999; 58:459–471.PubMedCrossRefGoogle Scholar
  75. 75.
    Lindholm D. Role of neurotrophins in preventing glutamate induced neuronal cell death. J Neurol 1994; 242:S16–S18.PubMedCrossRefGoogle Scholar
  76. 76.
    Sagot Y, Dubois-Dauphin M, Tan SA et al. Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J Neurosci 1995; 15:7727–7733.PubMedGoogle Scholar
  77. 77.
    Patel TD, Jackman A, Rice FL et al. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 2000; 25:345–357.PubMedCrossRefGoogle Scholar
  78. 78.
    McAllister AK, Katz LC, Lo DC. Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron 1997; 18:767–778.PubMedCrossRefGoogle Scholar
  79. 79.
    Leing rtner A, Heisenberg C-P, Kolbeck R et al. Brain-derived neurotrophic factor increases neurotrophin- 3 expression in cerebellar granule neurons. J Biol Chem 1994; 269:828–830.Google Scholar
  80. 80.
    Canossa M, Griesbeck O, Berninger B et al. Neurotrophin release by neurotrophins: Implications for activity-dependent neuronal plasticity. Proc Natl Acad Sci USA 1997; 94:13279–13286.PubMedCrossRefGoogle Scholar
  81. 81.
    Kr ttgen A, Mller JC, Heymach JV, Jr. et al. Neurotrophins induce release of neurotrophins by the regulated secretory pathway. Proc Natl Acad Sci USA 1998; 95:9614–9619.CrossRefGoogle Scholar
  82. 82.
    Causing CG, Gloster A, Aloyz R et al. Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 1997; 18:257–267.PubMedCrossRefGoogle Scholar
  83. 83.
    Giehl KM. Trophic dependencies of rodent corticospinal neurons. Rev Neurosci 2001; 12:79–94.PubMedGoogle Scholar
  84. 84.
    Merlio JP, Ernfors P, Kokaia Z et al. Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron 1993; 10:151–164.PubMedCrossRefGoogle Scholar
  85. 85.
    Kokaia Z, Andsberg G, Yan Q et al. Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: Evidence for increased synthesis and anterograde axonal transport. Exp Neurol 1998; 154:289–301.PubMedCrossRefGoogle Scholar
  86. 86.
    Beck T, Lindholm D, Castren E et al. Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus. J Cereb Blood Flow Metab 1994; 14:689–692.PubMedCrossRefGoogle Scholar
  87. 87.
    Tsukahara T, Yonekawa Y, Tanaka K et al. The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain. Neurosurgery 1994; 34:323–331.PubMedCrossRefGoogle Scholar
  88. 88.
    Chan KM, Lam DT, Pong K et al. Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion. Neurochem Res 1996; 21:763–767.PubMedCrossRefGoogle Scholar
  89. 89.
    Gall C, Lauterbom J, Bundman M et al. Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain. Epilepsy Res Suppl 1991; 4:225–245.PubMedGoogle Scholar
  90. 90.
    Ernfors P, Bengzon J, Kokaia Z et al. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 1991; 7:165–176.PubMedCrossRefGoogle Scholar
  91. 91.
    Mudo G, Jiang XH, timmusk t et al. Change in neurotrophins and their receptor mRNAs in the rat forebrain after status epilepticus induced by pilocarpine. Epilepsia 1996; 37:198–207.PubMedCrossRefGoogle Scholar
  92. 92.
    Binder DK, Routbort MJ, Ryan TE et al. Selective inhibition of kindling development by intraventricular administration of TrkB receptor body. J Neurosci 1999; 19:1424–1436.PubMedGoogle Scholar
  93. 93.
    Giehl KM, Tetzlaff W. BDNF and NT-3, but not NGF, prevent axotomy-induced death of rat corticospinal neurons in vivo. Eur J Neurosci 1996; 8:1167–1175.PubMedCrossRefGoogle Scholar
  94. 94.
    Schnell L, Schneider R, Kolbeck R et al. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 1994; 367:170–173.PubMedCrossRefGoogle Scholar
  95. 95.
    Hefti F, Weiner WJ. Nerve growth factor and Alzheimer s disease. Ann Neurol 1986; 20:275–281.PubMedCrossRefGoogle Scholar
  96. 96.
    Vazquez ME, Ebendal T. Messenger RNAs for trk and the low-affinity NGF receptor in rat basal forebrain. NeuroReport 1991; 2:593–596.PubMedCrossRefGoogle Scholar
  97. 97.
    Venero JL, Hefti F. TrkA NGF receptor expression by non-cholinergic thalamic neurons. NeuroReport 1993; 4:959–962.PubMedCrossRefGoogle Scholar
  98. 98.
    Hefti F, Lapchak PA. Pharmacology of nerve growth factor in the brain. Adv Pharmacol 1993; 24:239–273.PubMedCrossRefGoogle Scholar
  99. 99.
    Will B, Hefti F. Behavioural and neurochemical effects of chronic intraventricular injections of nerve growth factor in adult rats with fimbria lesions. Behav Brain Res 1985; 17:17–24.PubMedCrossRefGoogle Scholar
  100. 100.
    Fischer W, Wictorin K, Bjoerklund A et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987; 329:65–68.PubMedCrossRefGoogle Scholar
  101. 101.
    Markowska AL, Koliatsos VE, Breckler Si et al. Human nerve growth factor improves spatial memory in aged but not in young rats. J Neurosci 1994; 14:4815–4824.PubMedGoogle Scholar
  102. 102.
    Widmer HR, Knusel B, Hefti F. BDNF protection of basal forebrain cholinergic neurons after axotomy: complete protection of p75NGFR-positive cells. NeuroReport 1993; 4:363–366.PubMedCrossRefGoogle Scholar
  103. 103.
    Koliatsos VE, Price DL, Gouras GK et al. Highly selective effects of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 on intact and injured basal forebrain magnocellular neurons. J Comp Neurol 1994; 343:247–262.PubMedCrossRefGoogle Scholar
  104. 104.
    Fischer W, Sirevaag A, Wiegand Si et al. Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor. Proc Natl Acad Sri USA 1994; 91:8607–8611.CrossRefGoogle Scholar
  105. 105.
    Kn sel 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 USA 1991; 88:961–965.CrossRefGoogle Scholar
  106. 106.
    Alderson RF, Wiegand SJ, Anderson KD et al. Neurotrophin-4/5 maintains the cholinergie phenotype of axotomized septal neurons. Eur J Neurosci 1996; 8:282–290.PubMedCrossRefGoogle Scholar
  107. 107.
    Phillips HS, Hains JM, Armanini M et al. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer s disease. Neuron 1991; 7:695–702.PubMedCrossRefGoogle Scholar
  108. 108.
    Peterson DA, Leppert JT, Lee KF et al. Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75. Science 1997; 277:837–838.PubMedCrossRefGoogle Scholar
  109. 109.
    Hagg T, Van der Zee CEEM, Ross GM et al. Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75 Response. Science 1997; 277:838–839.Google Scholar
  110. 110.
    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; 4:79–95.PubMedCrossRefGoogle Scholar
  111. 111.
    Eriksdotter JM, Nordberg A, Amberla K et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer s disease. Dement Geriatr Cogn Disord 1998; 9:246–257.CrossRefGoogle Scholar
  112. 112.
    Hyman C, Hofer M, Barde Y-A et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350:230–232.PubMedCrossRefGoogle Scholar
  113. 113.
    Spina MB, Squint) SP, Miller J et al. Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: Involvement of the glutathione system. J Neurochem 1992; 59:99–106.PubMedCrossRefGoogle Scholar
  114. 114.
    Knusel B, Beck KD, Winslow JW et al. Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J Neurosci 1992; 12:4391–4402.PubMedGoogle Scholar
  115. 115.
    Hagg T. Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo. Exp Neurol 1998; 149:183–192.PubMedCrossRefGoogle Scholar
  116. 116.
    Altar CA, Boylan CB, Jackson C et al. Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. Proc Natl Acad Sci USA 1992; 89:11347–11351.PubMedCrossRefGoogle Scholar
  117. 117.
    Lapchak PA, Beck KD, Araujo DM et al. Chronic intranigral administration of brain-derived neurotrophic factor produces striatal dopaminergic hypofunction in unlesioned adult rats and fails to attenuate the decline of striatal dopaminergic function following medial forebrain bundle transection. Neuroscience 1993; 53:639–650.PubMedCrossRefGoogle Scholar
  118. 118.
    Ringstedt T, Lagercrantz H, Persson H. Expression of members of the trk family in the developing postnatal rat brain. Dev Brain Res 1993; 72:119–131.CrossRefGoogle Scholar
  119. 119.
    Numan S, Seroogy KB. Expression of TrkB and TrkC mRNAs by adult midbrain dopamine neurons: A double-label in situ hybridization study. J Comp Neurol 1999; 403:295–308.PubMedCrossRefGoogle Scholar
  120. 120.
    Koliatsos VE, Clatterbuck RE, Winslow JW et al. Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 1993; 10:359–367.PubMedCrossRefGoogle Scholar
  121. 121.
    Klein R, Smeyne RJ, Wurst W et al. Targeted disruption of the TrkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 1993; 75:113–122.PubMedGoogle Scholar
  122. 122.
    Liu X, Ernfors P, Wu H et al. Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature 1995; 375:238–241.PubMedCrossRefGoogle Scholar
  123. 123.
    Conover JC, Erickson JT, Katz DM et al. Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature 1995; 375:235–238.PubMedCrossRefGoogle Scholar
  124. 124.
    Kobayashi NR, Bedard AM, Hincke MT et al. Increased expression of BDNF and TrkB mRNA in rat facial motoneurons after axotomy. Eur J Neurosci 1996; 8:1018–1029.PubMedCrossRefGoogle Scholar
  125. 125.
    Sendtner M, Holtmann B, Hughes RA. The response of motoneurons to neurotrophins. Neurochem Res 1996; 21:831–841.PubMedCrossRefGoogle Scholar
  126. 126.
    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; 360:757–759.PubMedCrossRefGoogle Scholar
  127. 127.
    Yan Q, Elliott J, Snider WD. Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 1992; 360:753–755.PubMedCrossRefGoogle Scholar
  128. 128.
    Johnson JE, Qin-Wei Y, Prevette D et al. Brain-derived proteins that rescue spinal motoneurons from cell death in the chick embryo: Comparisons with target-derived and recombinant factors. J Neurobiol 1995; 27;573–589.PubMedCrossRefGoogle Scholar
  129. 129.
    Yan Q, Matheson C, Lopez OT et al. The biological responses of axotomized adult motoneurons to brain-derived neurotrophic factor. J Neurosci 1994; 14:5281–5291.PubMedGoogle Scholar
  130. 130.
    Ernfors P, Henschen A, Olson L et al. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 1989; 2:1605–1613.PubMedCrossRefGoogle Scholar
  131. 131.
    Koliatsos VE, Crawford TO, Price DL. Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. Brain Res 1991; 549:297–304.PubMedCrossRefGoogle Scholar
  132. 132.
    Frade JM, Barde YA. Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development 1999; 126:683–690.PubMedGoogle Scholar
  133. 133.
    Ferri CC, Moore FA, Bisby MA. Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor. Journal of Neurobiology 1998; 34:1–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Yan Q, Miller JA. The use of trophic factors in degenerative motoneuron diseases. Exp Neurol 1993; 124:60–63.PubMedCrossRefGoogle Scholar
  135. 135.
    Stoeckel K, Guroff G, Schwab M et al. The significance of retrograde axonal transport for the accumulation of systemically administered nerve growth factor (NGF) in the rat superior cervical ganglion. Brain Res 1976; 109:271–284.PubMedCrossRefGoogle Scholar
  136. 136.
    Curtis R, Tonra JR, Stark JL et al. Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms. Mol Cell Neurosci 1998; 12:105–118.PubMedCrossRefGoogle Scholar
  137. 137.
    Ochs G, Penn RD, Giess R et al. A trial of recombinant methionyl human Brain-Derived Neurotrophic Factor (BDNF) given by intrathecal (IT) infusion to patients with Amyotrophic Lateral Sclerosis (ALS). Neurology 1998; A246.Google Scholar
  138. 138.
    Phillips HS, Armanini MP. Expression of the trk family of neurotrophin receptors in developing and adult dorsal root ganglion neurons. Philos Trans R Soc Lond B Biol Sci 1996; 351:413–416.PubMedCrossRefGoogle Scholar
  139. 139.
    Karchewski LA, Kim FA, Johnston J et al. Anatomical evidence supporting the potential for modulation by multiple neurotrophins in the majority of adult lumbar sensory neurons. J Comp Neurol 1999; 413:327–341.PubMedCrossRefGoogle Scholar
  140. 140.
    Lindsay RM. Nerve growth factors (NGF, BDNF) enhance axonal regeneration but are not required for survival of adult sensory neurons. J Neurosci 1988; 8:2394–2405.PubMedGoogle Scholar
  141. 141.
    Lindsay RM, Harmar AJ. Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons. Nature 1989; 337:362–364.PubMedCrossRefGoogle Scholar
  142. 142.
    Mendell LM. Neurotrophin action on sensory neurons in adults: an extension of the neurotrophic hypothesis. Pain 1999; Suppl 6:S127–S132.CrossRefGoogle Scholar
  143. 143.
    Verge VM, Gratto KA, Karchewski LA et al. Neurotrophins and nerve injury in the adult. Philos Trans R Soc Lond B Biol Sci 1996; 351:423–430.PubMedCrossRefGoogle Scholar
  144. 144.
    Anand P. Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol Sci 1996; 351:449–454.PubMedCrossRefGoogle Scholar
  145. 145.
    Lewin GR. Neurotrophins and the specification o neuronal phenotype. Phil Trans R Soc London 1996;405–411.Google Scholar
  146. 146.
    Gao WQ, Dybdal N, Shinsky N et al. Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy. Ann Neurol 1995; 38:30–37.PubMedCrossRefGoogle Scholar
  147. 147.
    Apfel SC, Arezzo JC, Lipson L et al. Nerve growth factor prevents experimental cisplatin neuropathy. Ann Neurol 1992; 31:76–80.PubMedCrossRefGoogle Scholar
  148. 148.
    Ernfors P, Van De WT, Loring J et al. Complementary roles of BDNF and NT-3 in vestibular and auditory development. Neuron 1995; 14:1153–1164.PubMedCrossRefGoogle Scholar
  149. 149.
    Ernfors P, Duan ML, Elshamy WM et al. Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3. Nat Med 1996; 2:463–467.PubMedCrossRefGoogle Scholar
  150. 150.
    Staecker H, Kopke R, Malgrange B et al. NT-3 and/or BDNF therapy prevents loss of auditory neurons following loss of hair cells. NeuroReport 1996; 7:889–894.PubMedCrossRefGoogle Scholar
  151. 151.
    Chalazonitis A, Rothman TP, Chen J et al. Neurotrophin-3 induces neural crest-derived cells from fetal rat gut to develop in vitro as neurons or glia. J Neurosci 1994; 14:6571–6584.PubMedGoogle Scholar
  152. 152.
    Sternini C, Su D, Arakawa J et al. Cellular localization of Pan-trk immunoreactivity and TrkC mRNA in the enteric nervous system. J Comp Neurol 1996; 368:597–607.PubMedCrossRefGoogle Scholar
  153. 153.
    McArthur JC, Yiannoutsos C, Simpson DM et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 2000; 54:1080–1088.PubMedCrossRefGoogle Scholar
  154. 154.
    Apfel SC, Kessler JA, Adornato BT et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 1998; 51:695–702.PubMedCrossRefGoogle Scholar
  155. 155.
    Apfel SC, Schwartz S, Adornato BT et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. JAMA 2000; 284:2215–2221.PubMedCrossRefGoogle Scholar
  156. 156.
    Petty BG, Cornblath DR, Adornato BT et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994; 36:244–246.PubMedCrossRefGoogle Scholar
  157. 157.
    Mazurek N, Weskamp G, Eme P et al. Nerve growth factor induces mast cell degranulation without changing intracellular calcium levels. FEBS Lett 1986; 198:315–320.PubMedCrossRefGoogle Scholar
  158. 158.
    Chuang H, Prescott ED, Kong H et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 2001; 411:957–962.PubMedCrossRefGoogle Scholar
  159. 159.
    Lambiase A, Rama P, Bonini S et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med 1998; 338:1174–1180.PubMedCrossRefGoogle Scholar
  160. 160.
    Tuveri M, Generini S, Matucci-Cerinic M et al. NGF, a useful tool in the treatment of chronic vasculitic ulcers in rheumatoid arthritis. Lancet 2000; 356:1739–1740.PubMedCrossRefGoogle Scholar
  161. 161.
    Siuciak JA, Clark MS, Rind HB et al. BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J Neurosci Res 1998; 52:149–158.PubMedCrossRefGoogle Scholar
  162. 162.
    Gaiter D, Unsicker K. Sequential activation of the 5-HT1A serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Mol Cell Neurosci 2000; 15:446–455.CrossRefGoogle Scholar
  163. 163.
    Arenas E, Persson H. Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo. Nature 1994; 367:368–371.PubMedCrossRefGoogle Scholar
  164. 164.
    Pelleymounter MA, Cullen MJ, Wellman CL. Characteristics of BDNF-induced weight loss. Exp Neurol 1995; 131:229–238.PubMedCrossRefGoogle Scholar
  165. 165.
    Mamounas LA, Altar CA, Blue ME et al. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 2000; 20:771–782.PubMedGoogle Scholar
  166. 166.
    Shen RY, Altar CA, Chiodo LA. Brain-derived neurotrophic factor increases the electrical activity of pars compacta dopamine neurons in vivo. Proc Natl Acad Sci USA 1994; 91:8920–8924.PubMedCrossRefGoogle Scholar
  167. 167.
    Celada P, Siuciak JA, Tran TM et al. Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphe serotonergic neurons. Brain Res 1996; 712:293–298.PubMedCrossRefGoogle Scholar
  168. 168.
    Martin-Iverson MT, Todd KG, Altar CA. Brain-derived neurotrophic factor and neurotrophin3 activate striatal dopamine and serotonin metabolism and related behaviors: Interactions with amphetamine. J Neurosci 1994; 14:1262–1270.PubMedGoogle Scholar
  169. 169.
    Lyons WE, Mamounas LA, Ricaurte GA et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 1999; 96:15239–15244.PubMedCrossRefGoogle Scholar
  170. 170.
    Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. EMBO J 2000; 19:1290–1300.PubMedCrossRefGoogle Scholar
  171. 171.
    Kafitz KW, Rose CR, Thoenen H et al. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 1999; 401:918–921.PubMedCrossRefGoogle Scholar
  172. 172.
    Lohof AM, Ip NY, Poo M. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 1993; 363:350–353.PubMedCrossRefGoogle Scholar
  173. 173.
    Jovanovic JN, Czernik AJ, Fienberg AA et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 2000; 3:323–329.PubMedCrossRefGoogle Scholar
  174. 174.
    Ruit KG, Osborne PA, Schmidt RE et al. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. J Neurosci 1990; 10:2412–2419.PubMedGoogle Scholar
  175. 175.
    McAllister AK, Lo DC, Katz LC. Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 1995; 15:791–803.PubMedCrossRefGoogle Scholar
  176. 176.
    Korte M, Carroll P, Wolf E et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 1995; 92:8856–8860.PubMedCrossRefGoogle Scholar
  177. 177.
    Minichiello L, Korte M, Wolfer D et al. Essential role for TrkB receptors in hippocampusmediated learning. Neuron 1999; 24:401–414.PubMedCrossRefGoogle Scholar
  178. 178.
    Duman RS, Vaidya VA, Nibuya M et al. Stress, antidepressant treatments, and neurotrophic factors: Molecular and cellular mechanisms. The Neuroscientist 1995; 6:351–360.CrossRefGoogle Scholar
  179. 179.
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psych 1997; 54:597–606.CrossRefGoogle Scholar
  180. 180.
    Siuciak JA, Lewis DR, Wiegand SJ et al. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56:131–137.PubMedCrossRefGoogle Scholar
  181. 181.
    Marty S, Berzaghi MD, berninger b. Neurotrophins and activity-dependent plasticity of cortical interneurons. Trends Neurosci 1997; 20:198–202.PubMedCrossRefGoogle Scholar
  182. 182.
    Adams B, Sazgar M, Osehobo P et al. Nerve growth factor accelerates seizure development, enhances mossy fiber sprouting, and attenuates seizure-induced decreases in neuronal density in the kindling model of epilepsy. J Neurosci 1997; 17:5288–5296.PubMedGoogle Scholar
  183. 183.
    Van der Ze CE, Rashid K, Le K et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J Neurosci 1995; 15: 5316–5323.Google Scholar
  184. 184.
    Reibel S, Larmet Y, Le BT et al. Brain-derived neurotrophic factor delays hippocampal kindling in the rat. Neuroscience 2000; 100:777–788.PubMedCrossRefGoogle Scholar
  185. 185.
    Anton ES, Weskamp G, Reichardt LF et al. Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci USA 1994; 91:2795–2799.PubMedCrossRefGoogle Scholar
  186. 186.
    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
  187. 187.
    Barres BA, Raff MC, Geese F et al. A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 1994; 367:371–375.PubMedCrossRefGoogle Scholar
  188. 188.
    McTigue DM, Homer PJ, Stokes BT et al. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 1998; 18:5354–5365.PubMedGoogle Scholar
  189. 189.
    Syroid DE, Maycox PJ, Soilu-Hanninen M et al. Induction of postnatal schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy. J Neurosci 2000; 20:5741–5747.PubMedGoogle Scholar
  190. 190.
    Torcia M, Bracci-Laudiero L, Lucibello M et al. Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 1996; 85:345–356.PubMedCrossRefGoogle Scholar
  191. 191.
    Kimata H, Yoshida A, Ishioka C et al. Nerve growth factor specifically induces human IgG4 production. Eur J Immunol 1991; 21:137–141.PubMedCrossRefGoogle Scholar
  192. 192.
    Neumann H, Misgeld T, Matsumuro K et al. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc Natl Acad Sci USA 1998; 95:5779–5784.PubMedCrossRefGoogle Scholar
  193. 193.
    Flugel A, Matsumuro K, Neumann H et al. Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur J Immunol 2001; 31:11–22.PubMedCrossRefGoogle Scholar
  194. 194.
    Villoslada P, Hauser SL, Bartke I et al. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 2000; 191:1799–1806.PubMedCrossRefGoogle Scholar
  195. 195.
    Donovan MJ, Lin MI, Wiegn P et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 2000; 127:4531–4540.PubMedGoogle Scholar
  196. 196.
    Donovan MJ, Hahn R, Tessarollo L et al. Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development. Nat Genetics 1996; 14:210–213.CrossRefGoogle Scholar
  197. 197.
    Donovan MJ, Miranda RC, Kraemer R et al. Neurotrophin and neurotrophin receptors in vascular smooth muscle cells. Regulation of expression in response to injury. Am J Pathol 1995; 147:309–324.PubMedGoogle Scholar
  198. 198.
    Ilag LL, Curtis R, Glass D et al. Pan-neurotrophin 1: a genetically engineered neurotrophic factor displaying multiple specificities in peripheral neurons in vitro and in vivo. Proc Natl Acad Sci USA 1995; 92:607–611.PubMedCrossRefGoogle Scholar
  199. 199.
    Urfer R, TsoulFas P, Soppet D et al. The binding epitopes of neurotrophin-3 to its receptors TrkC and gp75 and the design of a multifunctional human neurotrophin. EMBO J 1994; 13:5896–5909.PubMedGoogle Scholar
  200. 200.
    Friedman WJ, Black IB, Persson H et al. Synergistic trophic actions on rat basal forebrain neurons revealed by a synthetic NGF/BDNF chimaeric molecule. Eur J Neurosci 1995; 7: 656–662.PubMedCrossRefGoogle Scholar
  201. 201.
    Ryden M, Murray-Rust J, Glass D et al. Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling. EMBO J 1995; 14:1979–1990.PubMedGoogle Scholar
  202. 202.
    Saragovi HU, Gehring K. Development of pharmacological agents for targeting neurotrophins and their receptors. Trends Pharmacol Sci 2000; 21:93–98.PubMedCrossRefGoogle Scholar
  203. 203.
    LeSauteur L, Maliartchouk S, Le Jeune H et al. Potent human p140-TrkA agonists derived from an anti-receptor monoclonal antibody. J Neurosci 1996; 16:1308–1316.PubMedGoogle Scholar
  204. 204.
    Maliartchouk S, Feng Y, Ivanisevic L et al. A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors. Mol Pharmacol 2000; 57:385–391.PubMedGoogle Scholar
  205. 205.
    Treanor JJS, Schmelzer C, Knusel 13 et al. Heterodimeric neurotrophins induce phosphorylation of Trk receptors and promote neuronal differentiation in PC12 cells. J Biol Chem 1995; 270:23104–23110.PubMedCrossRefGoogle Scholar
  206. 206.
    Friden PM, Walus LR, Watson P et al. Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 1993; 259:373–377.PubMedCrossRefGoogle Scholar
  207. 207.
    Hefti F. Pharmacology of neurotrophic factors. Annu Rev Pharmacol Toxicol 1997; 37:239–267.PubMedCrossRefGoogle Scholar
  208. 208.
    Saudou F, Finkbeiner S, Devys D et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95:55–66.PubMedCrossRefGoogle Scholar
  209. 209.
    Shieh PB, Ghosh A. Molecular mechanisms underlying activity-dependent regulation of BDNF expression. J Neurobiol 1999; 41:127–134.PubMedCrossRefGoogle Scholar
  210. 210.
    Timmusk T, Palm K, Metsis M et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 1993; 10:475–489.PubMedCrossRefGoogle Scholar
  211. 211.
    Ma L, Merenmies J, Parada LF. Molecular characterization of the TrkA/NGF receptor minimal enhancer reveals regulation by multiple cis elements to drive embryonic neuron expression. Development 2000; 127:3777–3788.PubMedGoogle Scholar
  212. 212.
    Pan W, Banks WA, Kastin Al. Permeability of the blood-brain barrier to neurotrophins. Brain Res 1998; 788:87–94.PubMedCrossRefGoogle Scholar
  213. 213.
    Gravel C, Gotz R, Lorrain A et al. Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat Med 1997; 3:765–770.PubMedCrossRefGoogle Scholar
  214. 214.
    Mandel RJ, Gage FH, Clevenger DG et al. Nerve growth factor expressed in the medial septum following in vivo gene delivery using a recombinant adeno-associated viral vector protects cholinergic neurons from fimbria-fornix lesion-induced degeneration. Exp Neurol 1999; 155:59–64.PubMedCrossRefGoogle Scholar
  215. 215.
    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; 290:767–773.PubMedCrossRefGoogle Scholar
  216. 216.
    Flugel A, Willem M, Berkowicz T et al. Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses. Nat Med 1999; 5:843–847.PubMedCrossRefGoogle Scholar
  217. 217.
    Hoffman D, Wahlberg L, Aebischer P. NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria-fornix lesion. Exp Neurol 1990; 110:39–44.PubMedCrossRefGoogle Scholar
  218. 218.
    Shibayama M, Hattori S, Himes BT et al. Neurotrophin-3 prevents death of axotomized Clarke s nucleus neurons in adult rat. J Comp Neurol 1998; 390:102–111.PubMedCrossRefGoogle Scholar
  219. 219.
    Hoffman D, Breakefield XO, Short MP et al. Transplantation of a polymer-encapsulated cell line genetically engineered to release NGF. Exp Neurol 1993; 122:100–106.PubMedCrossRefGoogle Scholar
  220. 220.
    Winn SR, Hammang JP, Emerich DF et al. Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons. Proc Natl Acad Sci USA 1994; 91.2324–2328.PubMedCrossRefGoogle Scholar
  221. 221.
    Haase G, Kennel P, Pettmann B et al. Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nat Med 1997; 3:429–436.PubMedCrossRefGoogle Scholar
  222. 222.
    Sendtner M. Gene therapy for motor neuron disease. Nat Med 1997; 3:380–381.PubMedCrossRefGoogle Scholar
  223. 223.
    Sagot Y, Rosse T, Vejsada R et al. Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease. J Neurosci 1998; 18:1132–1141.PubMedGoogle Scholar
  224. 224.
    Nagatsu T, Mogi M, Ichinose H et al. Changes in cytokines and neurotrophins in Parkinson s disease. J Neural Transm Suppl 2000;277–290.Google Scholar
  225. 225.
    Vicario-Abejon C, Johe KK, Hazel TG et al. Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons. Neuron 1995; 15:105–114.PubMedCrossRefGoogle Scholar
  226. 226.
    Vicario-Abejon C, Collin C, TsoulFas P et al. Hippocampal stem cells differentiate into excitatory and inhibitory neurons. Eur J Neurosci 2000; 12:677–688.PubMedCrossRefGoogle Scholar
  227. 227.
    Leventhal C, Rafii S, Rafii D et al. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci 1999; 13:450–464.PubMedCrossRefGoogle Scholar
  228. 228.
    Rubio F, Kokaia Z, Arco A et al. BDNF gene transfer to the mammalian brain using CNSderived neural precursors. Gene Ther 1999; 6:1851–1866.PubMedCrossRefGoogle Scholar
  229. 229.
    Martinez-Serrano A, Lundberg C, Horellou P et al. CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: Complete rescue of axotomized cholinergic neurons after transplantation into the septum. J Neurosci 1995; 15:5668–5680.PubMedGoogle Scholar
  230. 230.
    Moutsatsos IK, Turgeman G, Zhou S et al. Exogenously regulated stem cell-mediated gene therapy for bone regeneration. Mol Ther 2001; 3:449–461.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Georg Dechant
    • 1
  • Harald Neumann
    • 2
    • 3
  1. 1.NeurobiochemistryMax-Planck-Institute of NeurobiologyMartinsriedGermany
  2. 2.NeuroimmunologyMax-Planck-Institute of NeurobiologyMartinsriedGermany
  3. 3.NeuroimmunologyEuropean Neuroscience Institute G ttingenG ttingenGermany

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