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Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease

Key Points

  • Neurotrophins bind to several combinations of cell surface receptors to regulate neuronal survival, function and plasticity.

  • The p75 neurotrophin receptor has numerous functions and is not just a 'death' receptor; under some circumstances it may counteract neurodegenerative signalling.

  • Potential factors that limit the application of neurotrophins as neurological therapeutics include their limited stability, poor central nervous system (CNS) bioavailability, binding to multiple (rather than individual) neurotrophin receptors and mechanism-based side effects.

  • Studies using synthetic oligopeptides have demonstrated the feasibility of creating small molecules that can act as ligands for neurotrophin receptors.

  • Small-molecule ligands can be targeted to specific neurotrophin receptors to modulate signalling.

  • Ligands have been developed that mimic, partially mimic or inhibit the actions of neurotrophins and, importantly, achieve effects that are distinct from those of neurotrophins.

  • Small-molecule modulation of neurotrophin receptor signalling can correct or counteract the deleterious intracellular signalling patterns that exist in various neuropathological states.

  • The administration of small-molecule ligands to several in vivo neurological disease models can correct neuropathological and behavioural abnormalities.

  • Small-molecule ligands are in early stages of clinical development.

Abstract

Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.

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Figure 1: Neurotrophins, their receptors and signalling pathways.
Figure 2: Neurotrophin signalling and pathological effects.

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References

  1. Chao, M. V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature Rev. Neurosci. 4, 299–309 (2003).

    CAS  Google Scholar 

  2. Reichardt, L. F. Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. B 361, 1545–1564 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Allen, S. J. & Dawbarn, D. Clinical relevance of the neurotrophins and their receptors. Clin. Sci. 110, 175–191 (2006).

    CAS  Google Scholar 

  4. Chao, M. V., Rajagopal, R. & Lee, F. S. Neurotrophin signalling in health and disease. Clin. Sci. 110, 167–173 (2006).

    CAS  Google Scholar 

  5. Poduslo, J. F. & Curran, G. L. Permeability at the blood–brain and blood–nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res. Mol. Brain Res. 36, 280–286 (1996).

    CAS  PubMed  Google Scholar 

  6. Saltzman, W. M., Mak, M. W., Mahoney, M. J., Duenas, E. T. & Cleland, J. L. Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems. Pharm. Res. 16, 232–240 (1999).

    CAS  PubMed  Google Scholar 

  7. Pardridge, W. M. Neurotrophins, neuroprotection and the blood–brain barrier. Curr. Opin. Investig. Drugs 3, 1753–1757 (2002).

    CAS  PubMed  Google Scholar 

  8. Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M. D. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol. Cell Neurosci. 18, 210–220 (2001).

    CAS  PubMed  Google Scholar 

  9. Mufson, E. J. et al. Hippocampal proNGF signaling pathways and β-amyloid levels in mild cognitive impairment and Alzheimer disease. J. Neuropathol. Exp. Neurol. 71, 1018–1029 (2012).

    CAS  PubMed  Google Scholar 

  10. Dyck, P. J. et al. Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 48, 501–505 (1997).

    CAS  PubMed  Google Scholar 

  11. Bergmann, I., Reiter, R., Toyka, K. V. & Koltzenburg, M. Nerve growth factor evokes hyperalgesia in mice lacking the low-affinity neurotrophin receptor p75. Neurosci. Lett. 255, 87–90 (1998).

    CAS  PubMed  Google Scholar 

  12. Aboulkassim, T. et al. Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory. Mol. Pharmacol. 80, 498–508 (2011).

    CAS  PubMed  Google Scholar 

  13. Capsoni, S. et al. Taking pain out of NGF: a “painless” NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PLoS ONE 6, e17321 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bai, Y. et al. An agonistic TrkB mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma. Invest. Ophthalmol. Vis. Sci. 51, 4722–4731 (2010).

    PubMed  Google Scholar 

  15. Guillemard, V. et al. An agonistic mAb directed to the TrkC receptor juxtamembrane region defines a trophic hot spot and interactions with p75 coreceptors. Dev. Neurobiol. 70, 150–164 (2010).

    CAS  PubMed  Google Scholar 

  16. Ugolini, G., Marinelli, S., Covaceuszach, S., Cattaneo, A. & Pavone, F. The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain. Proc. Natl Acad. Sci. USA 104, 2985–2990 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sahenk, Z. et al. TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in Trembler J mice. Exp. Neurol. 224, 495–506 (2010).

    CAS  PubMed  Google Scholar 

  18. Blesch, A., Uy, H. S., Diergardt, N. & Tuszynski, M. H. Neurite outgrowth can be modulated in vitro using a tetracycline-repressible gene therapy vector expressing human nerve growth factor. J. Neurosci. Res. 59, 402–409 (2000).

    CAS  PubMed  Google Scholar 

  19. Taylor, L., Jones, L., Tuszynski, M. H. & Blesch, A. Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord. J. Neurosci. 26, 9713–9721 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nagahara, A. H. et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature Med. 15, 331–337 (2009).

    CAS  PubMed  Google Scholar 

  21. Chattopadhyay, M. et al. Long-term neuroprotection achieved with latency-associated promoter-driven herpes simplex virus gene transfer to the peripheral nervous system. Mol. Ther. 12, 307–313 (2005).

    CAS  PubMed  Google Scholar 

  22. Lessmann, V. & Brigadski, T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci. Res. 65, 11–22 (2009).

    CAS  PubMed  Google Scholar 

  23. Santos, A. R., Comprido, D. & Duarte, C. B. Regulation of local translation at the synapse by BDNF. Prog. Neurobiol. 92, 505–516 (2010).

    CAS  PubMed  Google Scholar 

  24. Skeldal, S., Matusica, D., Nykjaer, A. & Coulson, E. J. Proteolytic processing of the p75 neurotrophin receptor: a prerequisite for signalling? Neuronal life, growth and death signalling are crucially regulated by intra-membrane proteolysis and trafficking of p75NTR. Bioessays 33, 614–625 (2011).

    CAS  PubMed  Google Scholar 

  25. Fenner, B. M. Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev. 23, 15–24 (2012).

    CAS  PubMed  Google Scholar 

  26. Lessmann, V., Gottmann, K. & Malcangio, M. Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol. 69, 341–374 (2003).

    CAS  PubMed  Google Scholar 

  27. Bruno, M. A. & Cuello, A. C. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc. Natl Acad. Sci. USA 103, 6735–6740 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Feng, D. et al. Molecular and structural insight into proNGF engagement of p75NTR and sortilin. J. Mol. Biol. 396, 967–984 (2010).

    CAS  PubMed  Google Scholar 

  29. Roux, P. P., Bhakar, A. L., Kennedy, T. E. & Barker, P. A. The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J. Biol. Chem. 276, 23097–23104 (2001).

    CAS  PubMed  Google Scholar 

  30. Carter, B. D. et al. Selective activation of NF-κB by nerve growth factor through the neurotrophin receptor p75. Science 272, 542–545 (1996).

    CAS  PubMed  Google Scholar 

  31. Volonte, C., Angelastro, J. M. & Greene, L. A. Association of protein kinases ERK1 and ERK2 with p75 nerve growth factor receptors. J. Biol. Chem. 268, 21410–21415 (1993).

    CAS  PubMed  Google Scholar 

  32. Casaccia-Bonnefil, P., Carter, B. D., Dobrowsky, R. T. & Chao, M. V. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719 (1996).

    CAS  PubMed  Google Scholar 

  33. Yamashita, T., Tucker, K. L. & Barde, Y. A. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).

    CAS  PubMed  Google Scholar 

  34. Sachs, B. D. et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J. Cell Biol. 177, 1119–1132 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Le Moan, N., Houslay, D. M., Christian, F., Houslay, M. D. & Akassoglou, K. Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α. Mol. Cell 44, 476–490 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Dobrowsky, R. T., Werner, M. H., Castellino, A. M., Chao, M. V. & Hannun, Y. A. Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. Science 265, 1596–1599 (1994).

    CAS  PubMed  Google Scholar 

  37. Barbacid, M. Structural and functional properties of the TRK family of neurotrophin receptors. Ann. NY Acad. Sci. 766, 442–458 (1995).

    CAS  PubMed  Google Scholar 

  38. Huang, E. J. & Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

    CAS  PubMed  Google Scholar 

  39. Ip, N. Y. et al. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc. Natl Acad. Sci. USA 89, 3060–3064 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Brodeur, G. M. et al. Trk receptor expression and inhibition in neuroblastomas. Clin. Cancer Res. 15, 3244–3250 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bronfman, F. C., Tcherpakov, M., Jovin, T. M. & Fainzilber, M. Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome. J. Neurosci. 23, 3209–3220 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Grimes, M. L., Beattie, E. & Mobley, W. C. A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl Acad. Sci. USA 94, 9909–9914 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ginty, D. D. & Segal, R. A. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr. Opin. Neurobiol. 12, 268–274 (2002).

    CAS  PubMed  Google Scholar 

  44. Vesa, J., Kruttgen, A. & Shooter, E. M. p75 reduces TrkB tyrosine autophosphorylation in response to brain- derived neurotrophic factor and neurotrophin 4/5. J. Biol. Chem. 275, 24414–24420 (2000).

    CAS  PubMed  Google Scholar 

  45. Barker, P. A. High affinity not in the vicinity? Neuron 53, 1–4 (2007).

    CAS  PubMed  Google Scholar 

  46. Urra, S. et al. TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal γ-secretase-mediated release of the p75 intracellular domain. J. Biol. Chem. 282, 7606–7615 (2007).

    CAS  PubMed  Google Scholar 

  47. Ceni, C. et al. The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling. J. Cell Sci. 123, 2299–2307 (2010).

    CAS  PubMed  Google Scholar 

  48. He, X. L. & Garcia, K. C. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304, 870–875 (2004).

    CAS  PubMed  Google Scholar 

  49. Wehrman, T. et al. Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron 53, 25–38 (2007).

    CAS  PubMed  Google Scholar 

  50. Iacaruso, M. F. et al. Structural model for p75NTR–TrkA intracellular domain interaction: a combined FRET and bioinformatics study. J. Mol. Biol. 414, 681–698 (2011).

    CAS  PubMed  Google Scholar 

  51. Matusica, D. et al. An intracellular domain fragment of the p75 neurotrophin receptor (p75NTR) enhances TrkA receptor function. J. Biol. Chem. 288, 11144–11154 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gong, Y., Cao, P., Yu, H. J. & Jiang, T. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 454, 789–793 (2008).

    CAS  PubMed  Google Scholar 

  53. Vilar, M. et al. Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor. J. Cell Sci. 122, 3351–3357 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Nykjaer, A. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004).

    CAS  PubMed  Google Scholar 

  55. Fahnestock, M. et al. The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor. J. Neurochem. 89, 581–592 (2004).

    CAS  PubMed  Google Scholar 

  56. Clewes, O. et al. Human ProNGF: biological effects and binding profiles at TrkA, p75NTR and sortilin. J. Neurochem. 107, 1124–1135 (2008).

    CAS  PubMed  Google Scholar 

  57. Masoudi, R. et al. Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors. J. Biol. Chem. 284, 18424–18433 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Unsain, N., Nunez, N., Anastasia, A. & Masco, D. H. Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: an initial event in neuronal injury induction. Neuroscience 154, 978–993 (2008).

    CAS  PubMed  Google Scholar 

  59. Volosin, M. et al. Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J. Neurosci. 26, 7756–7766 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Buttigieg, H., Kawaja, M. D. & Fahnestock, M. Neurotrophic activity of proNGF in vivo. Exp. Neurol. 204, 832–835 (2007).

    CAS  PubMed  Google Scholar 

  61. Mufson, E. J., Brashers-Krug, T. & Kordower, J. H. p75 nerve growth factor receptor immunoreactivity in the human brainstem and spinal cord. Brain Res. 589, 115–123 (1992).

    CAS  PubMed  Google Scholar 

  62. Kordower, J. H. & Mufson, E. J. NGF receptor (p75)-immunoreactivity in the developing primate basal ganglia. J. Comp. Neurol. 327, 359–375 (1993).

    CAS  PubMed  Google Scholar 

  63. Mrzljak, L. & Goldman-Rakic, P. S. Low-affinity nerve growth factor receptor (p75NGFR)- and choline acetyltransferase (ChAT)-immunoreactive axons in the cerebral cortex and hippocampus of adult macaque monkeys and humans. Cereb. Cortex 3, 133–147 (1993).

    CAS  PubMed  Google Scholar 

  64. Andsberg, G., Kokaia, Z. & Lindvall, O. Upregulation of p75 neurotrophin receptor after stroke in mice does not contribute to differential vulnerability of striatal neurons. Exp. Neurol. 169, 351–363 (2001).

    CAS  PubMed  Google Scholar 

  65. Beattie, M. S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Harrington, A. W. et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc. Natl Acad. Sci. USA 101, 6226–6230 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tep, C. et al. Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J. Neurosci. 33, 397–410 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Oh, J. D., Chartisathian, K., Chase, T. N. & Butcher, L. L. Overexpression of neurotrophin receptor p75 contributes to the excitotoxin-induced cholinergic neuronal death in rat basal forebrain. Brain Res. 853, 174–185 (2000).

    CAS  PubMed  Google Scholar 

  69. Angelo, M. F. et al. p75 NTR expression is induced in isolated neurons of the penumbra after ischemia by cortical devascularization. J. Neurosci. Res. 87, 1892–1903 (2009).

    CAS  PubMed  Google Scholar 

  70. Woo, N. H. et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nature Neurosci. 8, 1069–1077 (2005).

    CAS  PubMed  Google Scholar 

  71. Lochner, J. E. et al. Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity. Dev. Neurobiol. 68, 1243–1256 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Deinhardt, K. et al. Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac. Sci. Signal. 4, ra82 (2011).

    PubMed  PubMed Central  Google Scholar 

  73. Je, H. S. et al. Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. Proc. Natl Acad. Sci. USA 109, 15924–15929 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kotlyanskaya, L., McLinden, K. A. & Giniger, E. Of proneurotrophins and their antineurotrophic effects. Sci. Signal. 6, pe6 (2013).

    PubMed  PubMed Central  Google Scholar 

  75. Deinhardt, K., Reversi, A., Berninghausen, O., Hopkins, C. R. & Schiavo, G. Neurotrophins redirect p75NTR from a clathrin-independent to a clathrin-dependent endocytic pathway coupled to axonal transport. Traffic 8, 1736–1749 (2007).

    CAS  PubMed  Google Scholar 

  76. Terry, A. V. Jr., Kutiyanawalla, A. & Pillai, A. Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats. Physiol. Behav. 102, 149–157 (2011).

    CAS  PubMed  Google Scholar 

  77. Peng, S., Wuu, J., Mufson, E. J. & Fahnestock, M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropathol. Exp. Neurol. 63, 641–649 (2004).

    CAS  PubMed  Google Scholar 

  78. Wang, Y. J. et al. Effects of proNGF on neuronal viability, neurite growth and amyloid-β metabolism. Neurotox. Res. 17, 257–267 (2010).

    PubMed  Google Scholar 

  79. Le, A. P. & Friedman, W. J. Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J. Neurosci. 32, 703–712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cuello, A. C., Bruno, M. A., Allard, S., Leon, W. & Iulita, M. F. Cholinergic involvement in Alzheimer's disease. A link with NGF maturation and degradation. J. Mol. Neurosci. 40, 230–235 (2010).

    CAS  PubMed  Google Scholar 

  81. Serup Andersen, O. et al. Identification of a linear epitope in sortilin that partakes in pro-neurotrophin binding. J. Biol. Chem. 285, 12210–12222 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wiesmann, C., Ultsch, M. H., Bass, S. H. & de Vos, A. M. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401, 184–188 (1999).

    CAS  PubMed  Google Scholar 

  83. Banfield, M. J. et al. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure 9, 1191–1199 (2001).

    CAS  PubMed  Google Scholar 

  84. Ibanez, C. F. Emerging themes in structural biology of neurotrophic factors. Trends Neurosci. 21, 438–444 (1998).

    CAS  PubMed  Google Scholar 

  85. Arevalo, J. C. et al. TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor. Mol. Cell. Biol. 20, 5908–5916 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ohira, K., Shimizu, K. & Hayashi, M. TrkB dimerization during development of the prefrontal cortex of the macaque. J. Neurosci. Res. 65, 463–469 (2001).

    CAS  PubMed  Google Scholar 

  87. Mischel, P. S. et al. Nerve growth factor signals via preexisting TrkA receptor oligomers. Biophys. J. 83, 968–976 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Shen, J. & Maruyama, I. N. Nerve growth factor receptor TrkA exists as a preformed, yet inactive, dimer in living cells. FEBS Lett. 585, 295–299 (2011).

    CAS  PubMed  Google Scholar 

  89. Shen, J. & Maruyama, I. N. Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells. J. Mol. Signal. 7, 2 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tauszig-Delamasure, S. et al. The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm. Proc. Natl Acad. Sci. USA 104, 13361–13366 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Pitts, A. F. & Miller, M. W. Expression of nerve growth factor, p75, and trk in the somatosensory and motor cortices of mature rats: evidence for local trophic support circuits. Somatosens. Mot. Res. 12, 329–342 (1995).

    CAS  PubMed  Google Scholar 

  92. Vega, J. A. et al. Immunohistochemical localization of the high-affinity NGF receptor (gp140-trkA) in the adult human dorsal root and sympathetic ganglia and in the nerves and sensory corpuscles supplying digital skin. Anat. Rec. 240, 579–588 (1994).

    CAS  PubMed  Google Scholar 

  93. Boissiere, F., Faucheux, B., Ruberg, M., Agid, Y. & Hirsch, E. C. Decreased TrkA gene expression in cholinergic neurons of the striatum and basal forebrain of patients with Alzheimer's disease. Exp. Neurol. 145, 245–252 (1997).

    CAS  PubMed  Google Scholar 

  94. Sofroniew, M. V., Howe, C. L. & Mobley, W. C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281 (2001).

    CAS  PubMed  Google Scholar 

  95. Poo, M. M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–32 (2001).

    CAS  Google Scholar 

  96. Yamada, K. & Nabeshima, T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J. Pharmacol. Sci. 91, 267–270 (2003).

    CAS  PubMed  Google Scholar 

  97. Ernfors, P., Lee, K. F., Kucera, J. & Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77, 503–512 (1994).

    CAS  PubMed  Google Scholar 

  98. McMahon, S. B., Armanini, M. P., Ling, L. H. & Phillips, H. S. Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12, 1161–1171 (1994).

    CAS  PubMed  Google Scholar 

  99. Rabizadeh, S. & Bredesen, D. E. Ten years on: mediation of cell death by the common neurotrophin receptor p75NTR. Cytokine Growth Factor Rev. 14, 225–239 (2003).

    CAS  PubMed  Google Scholar 

  100. Bamji, S. X. et al. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J. Cell Biol. 140, 911–923 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Rabizadeh, S. et al. Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348 (1993).

    CAS  PubMed  Google Scholar 

  102. Bredesen, D. E. et al. p75NTR and the concept of cellular dependence: seeing how the other half die. Cell Death Differ. 5, 365–371 (1998).

    CAS  PubMed  Google Scholar 

  103. Roux, P. P. & Barker, P. A. Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol. 67, 203–233 (2002).

    CAS  PubMed  Google Scholar 

  104. Longo, F. M. & Massa, S. M. Small molecule modulation of p75 neurotrophin receptor functions. CNS Neurol. Disord. Drug Targets 7, 63–70 (2008).

    CAS  PubMed  Google Scholar 

  105. Yoon, S. O., Casaccia-Bonnefil, P., Carter, B. & Chao, M. V. Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J. Neurosci. 18, 3273–3281 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Esposito, D. et al. The cytoplasmic and transmembrane domains of the p75 and Trk A receptors regulate high affinity binding to nerve growth factor. J. Biol. Chem. 276, 32687–32695 (2001).

    CAS  PubMed  Google Scholar 

  107. Majdan, M., Walsh, G. S., Aloyz, R. & Miller, F. D. TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. J. Cell Biol. 155, 1275–1285 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Jung, K. M. et al. Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J. Biol. Chem. 278, 42161–42169 (2003).

    CAS  PubMed  Google Scholar 

  109. Epa, W. R., Markovska, K. & Barrett, G. L. The p75 neurotrophin receptor enhances TrkA signalling by binding to Shc and augmenting its phosphorylation. J. Neurochem. 89, 344–353 (2004).

    CAS  PubMed  Google Scholar 

  110. Wilson-Gerwing, T. D., Johnston, J. M. & Verge, V. M. p75 neurotrophin receptor is implicated in the ability of neurotrophin-3 to negatively modulate activated ERK1/2 signaling in TrkA-expressing adult sensory neurons. J. Comp. Neurol. 516, 49–58 (2009).

    CAS  PubMed  Google Scholar 

  111. Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature Neurosci. 7, 221–228 (2004).

    CAS  PubMed  Google Scholar 

  112. Wong, S. T. et al. A p75NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5, 1302–1308 (2002).

    CAS  PubMed  Google Scholar 

  113. Wang, K. C., Kim, J. A., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    CAS  PubMed  Google Scholar 

  114. Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    CAS  PubMed  Google Scholar 

  115. Chang, Q., Khare, G., Dani, V., Nelson, S. & Jaenisch, R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49, 341–348 (2006).

    CAS  PubMed  Google Scholar 

  116. Gharami, K., Xie, Y., An, J. J., Tonegawa, S. & Xu, B. Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington's disease phenotypes in mice. J. Neurochem. 105, 369–379 (2008).

    CAS  PubMed  Google Scholar 

  117. Larimore, J. L. et al. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol. Dis. 34, 199–211 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Harris, N. G., Mironova, Y. A., Hovda, D. A. & Sutton, R. L. Pericontusion axon sprouting is spatially and temporally consistent with a growth-permissive environment after traumatic brain injury. J. Neuropathol. Exp. Neurol. 69, 139–154 (2010).

    PubMed  Google Scholar 

  119. Boulle, F. et al. TrkB inhibition as a therapeutic target for CNS-related disorders. Prog. Neurobiol. 98, 197–206 (2012).

    CAS  PubMed  Google Scholar 

  120. He, X. P. et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 43, 31–42 (2004).

    CAS  PubMed  Google Scholar 

  121. Dinocourt, C., Gallagher, S. E. & Thompson, S. M. Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors. Eur. J. Neurosci. 24, 1857–1866 (2006).

    PubMed  Google Scholar 

  122. Yasui, M. et al. Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury. Eur. J. Pain 16, 953–965 (2012).

    CAS  PubMed  Google Scholar 

  123. McKelvey, L., Shorten, G. D. & O'Keeffe, G. W. Nerve growth factor-mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management. J. Neurochem. 124, 276–289 (2013).

    CAS  PubMed  Google Scholar 

  124. Scarpi, D. et al. Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity. Cell Death Dis. 3, e389 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Eibl, J. K., Strasser, B. C. & Ross, G. M. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem. Int. 61, 1266–1275 (2012).

    CAS  PubMed  Google Scholar 

  126. Heinrich, C. et al. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol. Dis. 42, 35–47 (2011).

    CAS  PubMed  Google Scholar 

  127. Jiang, G. & Hunter, T. Receptor signaling: when dimerization is not enough. Curr. Biol. 9, R568–R571 (1999).

    CAS  PubMed  Google Scholar 

  128. Livnah, O. et al. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283, 987–990 (1999).

    CAS  PubMed  Google Scholar 

  129. Remy, I., Wilson, I. A. & Michnick, S. W. Erythropoietin receptor activation by a ligand-induced conformation change. Science 283, 990–993 (1999).

    CAS  PubMed  Google Scholar 

  130. Couturier, C. & Jockers, R. Activation of the leptin receptor by a ligand-induced conformational change of constitutive receptor dimers. J. Biol. Chem. 278, 26604–26611 (2003).

    CAS  PubMed  Google Scholar 

  131. Ferguson, K. M. et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507–517 (2003).

    CAS  PubMed  Google Scholar 

  132. Schlessinger, J. Signal transduction. Autoinhibition control. Science 300, 750–752 (2003).

    CAS  PubMed  Google Scholar 

  133. Streaker, E. D., Gupta, A. & Beckett, D. The biotin repressor: thermodynamic coupling of corepressor binding, protein assembly, and sequence-specific DNA binding. Biochemistry 41, 14263–14271 (2002).

    CAS  PubMed  Google Scholar 

  134. Ivanov, I. et al. Ligand-induced formation of transient dimers of mammalian 12/15-lipoxygenase: a key to allosteric behavior of this class of enzymes? Proteins 80, 703–712 (2012).

    CAS  PubMed  Google Scholar 

  135. Arevalo, J. C. et al. A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. Oncogene 20, 1229–1234 (2001).

    CAS  PubMed  Google Scholar 

  136. Spiegel, K. et al. PD 90780, a non peptide inhibitor of nerve growth factor's binding to the P75 NGF receptor. Biochem. Biophys. Res. Commun. 217, 488–494 (1995).

    CAS  PubMed  Google Scholar 

  137. Jang, S. W. et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl Acad. Sci. USA 107, 2687–2692 (2010). This paper reports the identification of a flavinoid compound (7,8-DHF) that activates TRKB and that has subsequently been found to exhibit therapeutic effects in several mouse models of disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Jang, S. W. et al. Deoxygedunin, a natural product with potent neurotrophic activity in mice. PLoS ONE 5, e11528 (2010).

    PubMed  PubMed Central  Google Scholar 

  139. Massa, S. M. et al. Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J. Neurosci. 26, 5288–5300 (2006). This paper reports the first identification of small-molecule non-peptide p75NTR ligands that modulate p75NTR signalling towards survival in neurons and oligodendroglia.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Belliveau, D. J. et al. NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis. J. Cell Biol. 136, 375–388 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Saragovi, H. U. et al. A TrkA-selective, fast internalizing nerve growth factor-antibody complex induces trophic but not neuritogenic signals. J. Biol. Chem. 273, 34933–34940 (1998).

    CAS  PubMed  Google Scholar 

  142. Minichiello, L. et al. Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron 21, 335–345 (1998).

    CAS  PubMed  Google Scholar 

  143. Xie, Y. & Longo, F. M. Neurotrophin small-molecule mimetics. Prog. Brain Res. 128, 333–347 (2000).

    CAS  PubMed  Google Scholar 

  144. Pollack, S. J. & Harper, S. J. Small molecule Trk receptor agonists and other neurotrophic factor mimetics. Curr. Drug Target CNS Neurol. Disord. 1, 59–80 (2002).

    CAS  Google Scholar 

  145. Saragovi, H. U. & Zaccaro, M. C. Small molecule peptidomimetic ligands of neurotrophin receptors, identifying binding sites, activation sites and regulatory sites. Curr. Pharm. Des. 8, 2201–2216 (2002).

    CAS  PubMed  Google Scholar 

  146. Longo, F. M., Vu, T. K. & Mobley, W. C. The in vitro biological effect of nerve growth factor is inhibited by synthetic peptides. Cell Regul. 1, 189–195 (1990). This study is the first report of a synthetic peptide derived from NGF that can inhibit the neurotrophic activity of NGF and it illustrates the possibility of small-molecule modulation of neurotrophin signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Ibanez, C. F. et al. Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell 69, 329–341 (1992).

    CAS  PubMed  Google Scholar 

  148. Yaar, M. et al. A cyclic peptide that binds p75NTR protects neurones from beta amyloid (1-40)-induced cell death. Neuropathol. Appl. Neurobiol. 33, 533–543 (2007).

    CAS  PubMed  Google Scholar 

  149. Botchkarev, V. A., Yaar, M., Gilchrest, B. A. & Paus, R. p75 neurotrophin receptor antagonist retards apoptosis-driven hair follicle involution (catagen). J. Invest. Dermatol. 120, 168–169 (2003).

    CAS  PubMed  Google Scholar 

  150. Li, S. et al. Differential actions of nerve growth factor receptors TrkA and p75NTR in a rat model of epileptogenesis. Mol. Cell Neurosci. 29, 162–172 (2005).

    CAS  PubMed  Google Scholar 

  151. Lebrun-Julien, F., Morquette, B., Douillette, A., Saragovi, H. U. & Di Polo, A. Inhibition of p75NTR in glia potentiates TrkA-mediated survival of injured retinal ganglion cells. Mol. Cell Neurosci. 40, 410–420 (2009).

    CAS  PubMed  Google Scholar 

  152. LeSauteur, L., Wei, L., Gibbs, B. F. & Saragovi, H. U. Small peptide mimics of nerve growth factor bind TrkA receptors and affect biological responses. J. Biol. Chem. 270, 6564–6569 (1995). This paper reports the competitive inhibition of NGF–TRKA binding with cyclic oligopeptides from β-turn loop 1 and loop 4 of NGF; this study supports the feasibility of developing small molecules that bind to TRKA.

    CAS  PubMed  Google Scholar 

  153. Maliartchouk, S. et al. Genuine monovalent ligands of TrkA nerve growth factor receptors reveal a novel pharmacological mechanism of action. J. Biol. Chem. 275, 9946–9956 (2000).

    CAS  PubMed  Google Scholar 

  154. Xie, Y., Tisi, M. A., Yeo, T. T. & Longo, F. M. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J. Biol. Chem. 275, 29868–29874 (2000).

    CAS  PubMed  Google Scholar 

  155. Maliartchouk, S. et al. A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors. Mol. Pharmacol. 57, 385–391 (2000). This paper reports the development of a peptidomimetic ligand (compound D3) that is capable of activating TRKA and promoting neuronal survival. Compounds of this class are in clinical trials for ophthalmological disorders.

    CAS  PubMed  Google Scholar 

  156. Bruno, M. A. et al. Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA. J. Neurosci. 24, 8009–8018 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Shi, Z., Birman, E. & Saragovi, H. U. Neurotrophic rationale in glaucoma: a TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo. Dev. Neurobiol. 67, 884–894 (2007).

    CAS  PubMed  Google Scholar 

  158. Colangelo, A. M. et al. A new nerve growth factor-mimetic peptide active on neuropathic pain in rats. J. Neurosci. 28, 2698–2709 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. O'Leary, P. D. & Hughes, R. A. Structure–activity relationships of conformationally constrained peptide analogues of loop 2 of brain-derived neurotrophic factor. J. Neurochem. 70, 1712–1721 (1998).

    PubMed  Google Scholar 

  160. O'Leary, P. D. & Hughes, R. A. Design of potent peptide mimetics of brain-derived neurotrophic factor. J. Biol. Chem. 278, 25738–25744 (2003). This paper reports the synthesis of a tricyclic oligopeptide dimer based on a BDNF domain; this was the first BDNF-derived molecule to exhibit neurotrophic activity, and this study indicates the possibility of developing small molecules with BDNF-like activity.

    PubMed  Google Scholar 

  161. Cardenas- Aguayo Mdel, C., Kazim, S. F., Grundke-Iqbal, I. & Iqbal, K. Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures. PLoS ONE 8, e53596 (2013).

    Google Scholar 

  162. Fletcher, J. M. et al. Design of a conformationally defined and proteolytically stable circular mimetic of brain-derived neurotrophic factor. J. Biol. Chem. 283, 33375–33383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Xiao, J. et al. A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination. J. Neurochem. 125, 386–398 (2013).

    CAS  PubMed  Google Scholar 

  164. Cazorla, M. et al. Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice. PLoS ONE 5, e9777 (2010).

    PubMed  PubMed Central  Google Scholar 

  165. Pattarawarapan, M., Zaccaro, M. C., Saragovi, U. H. & Burgess, K. New templates for syntheses of ring-fused, C10 β-turn peptidomimetics leading to the first reported small-molecule mimic of neurotrophin-3. J. Med. Chem. 45, 4387–4390 (2002).

    CAS  PubMed  Google Scholar 

  166. Zhang, A. J., Khare, S., Gokulan, K., Linthicum, D. S. & Burgess, K. Dimeric β-turn peptidomimetics as ligands for the neurotrophin receptor TrkC. Bioorg. Med. Chem. Lett. 11, 207–210 (2001).

    CAS  PubMed  Google Scholar 

  167. Lin, B. et al. Neuroprotection by small molecule activators of the nerve growth factor receptor. J. Pharmacol. Exp. Ther. 322, 59–69 (2007).

    CAS  PubMed  Google Scholar 

  168. Jang, S. W. et al. Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death. Proc. Natl Acad. Sci. USA 104, 16329–16334 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang, B. et al. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 284, 974–977 (1999).

    CAS  PubMed  Google Scholar 

  170. Jang, S. W. et al. Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity. Chem. Biol. 16, 644–656 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Fuh, G., Li, B., Crowley, C., Cunningham, B. & Wells, J. A. Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J. Biol. Chem. 273, 11197–11204 (1998).

    CAS  PubMed  Google Scholar 

  172. Clackson, T. & Wells, J. A. A hot spot of binding energy in a hormone–receptor interface. Science 267, 383–386 (1995).

    CAS  PubMed  Google Scholar 

  173. Angell, Y., Chen, D., Brahimi, F., Saragovi, H. U. & Burgess, K. A combinatorial method for solution-phase synthesis of labeled bivalent β-turn mimics. J. Am. Chem. Soc. 130, 556–565 (2008).

    CAS  PubMed  Google Scholar 

  174. Chen, J. et al. Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci. Lett. 499, 181–185 (2011).

    CAS  PubMed  Google Scholar 

  175. Devi, L. & Ohno, M. 7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's disease. Neuropsychopharmacology 37, 434–444 (2012).

    CAS  PubMed  Google Scholar 

  176. Andero, R. et al. Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am. J. Psychiatry 168, 163–172 (2011).

    PubMed  Google Scholar 

  177. Andero, R., Daviu, N., Escorihuela, R. M., Nadal, R. & Armario, A. 7,8-dihydroxyflavone, a TrkB receptor agonist, blocks long-term spatial memory impairment caused by immobilization stress in rats. Hippocampus 22, 399–408 (2012).

    CAS  PubMed  Google Scholar 

  178. Zeng, Y. et al. Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. J. Neurosci. 31, 17800–17810 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Blugeot, A. et al. Vulnerability to depression: from brain neuroplasticity to identification of biomarkers. J. Neurosci. 31, 12889–12899 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Liu, X. et al. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J. Med. Chem. 53, 8274–8286 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Liu, X. et al. Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression. J. Med. Chem. 55, 8524–8537 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Johnson, R. A. et al. 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J. Appl. Physiol. 112, 704–710 (2012).

    CAS  PubMed  Google Scholar 

  183. Massa, S. M. et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J. Clin. Invest. 120, 1774–1785 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Schmid, D. A. et al. A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J. Neurosci. 32, 1803–1810 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Han, J. et al. Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke 43, 1918–1924 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Prince, D. A. et al. Epilepsy following cortical injury: cellular and molecular mechanisms as targets for potential prophylaxis. Epilepsia 50 (Suppl. 2), 30–40 (2009).

    PubMed  PubMed Central  Google Scholar 

  187. Li, H. et al. Targets for preventing epilepsy following cortical injury. Neurosci. Lett. 497, 172–176 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Cazorla, M. et al. Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. J. Clin. Invest. 121, 1846–1857 (2011). This studyestablishes the feasibility of developing drug-like TRKB antagonists and their application in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Spaeth, A. M., Kanoski, S. E., Hayes, M. R. & Grill, H. J. TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin. Am. J. Physiol. Endocrinol. Metab. 302, E1252–E1260 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Ren, Q. et al. Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine. Pharmacol. Biochem. Behav. 106, 124–127 (2013).

    CAS  PubMed  Google Scholar 

  191. Jang, S. W. et al. N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc. Natl Acad. Sci. USA 107, 3876–3881 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Shen, J. et al. N-acetyl serotonin derivatives as potent neuroprotectants for retinas. Proc. Natl Acad. Sci. USA 109, 3540–3545 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Chen, D. et al. Bivalent peptidomimetic ligands of TrkC are biased agonists and selectively induce neuritogenesis or potentiate neurotrophin-3 trophic signals. ACS Chem. Biol. 4, 769–781 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Longo, F. M., Manthorpe, M., Xie, Y. M. & Varon, S. Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism. J. Neurosci. Res. 48, 1–17 (1997).

    CAS  PubMed  Google Scholar 

  195. Pehar, M. et al. Modulation of p75-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain. Eur. J. Neurosci. 24, 1575–1580 (2006).

    PubMed  Google Scholar 

  196. Yang, T. et al. Small molecule, non-peptide p75 ligands inhibit Aβ-induced neurodegeneration and synaptic impairment. PLoS ONE 3, e3604 (2008).

    PubMed  PubMed Central  Google Scholar 

  197. Knowles, J. K. et al. A small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol. Aging 34, 2052–2063 (2013).

    CAS  PubMed  Google Scholar 

  198. Bachis, A. & Mocchetti, I. Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins. Ann. NY Acad. Sci. 1053, 247–257 (2005).

    CAS  PubMed  Google Scholar 

  199. Meeker, R. B., Poulton, W., Feng, W. H., Hudson, L. & Longo, F. M. Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model. J. Neuroimmune Pharmacol. 7, 388–400 (2012).

    PubMed  Google Scholar 

  200. Lu, Q., Longo, F. M., Zhou, H., Massa, S. M. & Chen, Y. H. Signaling through Rho GTPase pathway as viable drug target. Curr. Med. Chem. 16, 1355–1365 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. James, S. E. et al. Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology 29, 605–612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Bai, Y. et al. Chronic and acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas p75NTR activity is neurotoxic through a paracrine mechanism. J. Biol. Chem. 285, 39392–39400 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nature Neurosci. 5, S1046–S1050 (2002).

    Google Scholar 

  204. Eriksdotter Jonhagen, M. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 9, 246–257 (1998).

    CAS  PubMed  Google Scholar 

  205. Jones, M. G., Munson, J. B. & Thompson, S. W. A role for nerve growth factor in sympathetic sprouting in rat dorsal root ganglia. Pain 79, 21–29 (1999).

    CAS  PubMed  Google Scholar 

  206. Pertovaara, A. Noradrenergic pain modulation. Prog. Neurobiol. 80, 53–83 (2006).

    CAS  PubMed  Google Scholar 

  207. Apfel, S. C. et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 284, 2215–2221 (2000).

    CAS  PubMed  Google Scholar 

  208. Wellmer, A., Misra, V. P., Sharief, M. K., Kopelman, P. G. & Anand, P. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J. Peripher. Nerv. Syst. 6, 204–210 (2001).

    CAS  PubMed  Google Scholar 

  209. McArthur, J. C. et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. Neurology 54, 1080–1088 (2000).

    CAS  PubMed  Google Scholar 

  210. Schifitto, G. et al. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 57, 1313–1316 (2001).

    CAS  PubMed  Google Scholar 

  211. [No authors listed.] A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 52, 1427–1433 (1999).

  212. Yaar, M. et al. Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. J. Clin. Invest. 100, 2333–2340 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Yaar, M. et al. Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J. Biol. Chem. 277, 7720–7725 (2002).

    CAS  PubMed  Google Scholar 

  214. Costantini, C. et al. Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death. J. Mol. Neurosci. 25, 141–156 (2005).

    CAS  PubMed  Google Scholar 

  215. Dinamarca, M. C., Rios, J. A. & Inestrosa, N. C. Postsynaptic receptors for amyloid-β oligomers as mediators of neuronal damage in Alzheimer's disease. Front. Physiol. 3, 464 (2012).

    PubMed  PubMed Central  Google Scholar 

  216. Shankar, G. M. & Walsh, D. M. Alzheimer's disease: synaptic dysfunction and Aβ. Mol. Neurodegener. 4, 48 (2009).

    PubMed  PubMed Central  Google Scholar 

  217. Shelton, D. L. et al. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J .Neurosci. 15, 477–491 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Jain, P. et al. An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye. Exp. Eye Res. 93, 503–512 (2011).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Work by the authors has been supported by grants from the following bodies: NIA UO1 AG032225 (to F.M.L.); the Alzheimer's Drug Discovery Foundation (to F.M.L.); the Alzheimer's Association (to F.M.L.); the Eastern Chapter of the North Carolina Alzheimer's Association (to F.M.L.); the Koret Foundation (to F.M.L.); the Taube Philanthropies (to F.M.L.); the Jean Perkins Foundation (to F.M.L.); the Horngren Family Alzheimer's Research Fund (to F.M.L.); the Richard M. Lucas Foundation (to F.M.L.); and the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (to S.M.M).

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Correspondence to Frank M. Longo or Stephen M. Massa.

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Competing interests

F.M.L. is founder of PharmatrophiX, a biotech company involved in developing small molecules targeted against neurotrophin receptors. F.M.L. and S.M.M. are also named inventors on patents for small molecules targeted against neurotrophin receptors.

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Neurotrophins and their Receptors in Disease States (PDF 272 kb)

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Glossary

Transactivating activators

Ligands that indirectly activate a given receptor through the activation of another receptor.

Secretagogues

Exogenous agents that increase the production or secretion of an endogenous agent.

Signalling adaptors

Proteins binding to activated receptors that mediate the activation of further intracellular signalling events.

Dominant negative

A term used to describe a situation whereby one protein isoform interferes with the effects of another.

Signalling endosomes

Endosomes containing ligand–receptor complexes that remain active, transducing cytoplasmic signals as they are transported within the cell.

Direct mechanisms

Interactions between transmembrane receptors that are mediated by direct contact with each other.

Bridged mechanisms

Interactions between transmembrane receptors that are mediated through an intermediary structure.

Proteolytic peptide-mediated mechanisms

Interactions between transmembrane receptors that are mediated through the cleavage, translocation and binding of a portion of one protein to the other.

Status epilepticus

Prolonged epileptic seizures that may result in excitotoxic injury.

Kindling-induced mossy fibre sprouting

Repetitive small seizures or other abnormal electrical activity leading to the growth of hippocampal dentate output axons, which enhance the likelihood of seizure activity.

Prepulse inhibition

A sequence of responses to stimuli in which a weaker stimulus inhibits the response to a subsequent stronger stimulus.

Acoustic startle

A reflexive motor response to a sudden, unexpected auditory stimulus.

Long-term potentiation

Prolonged strengthening of synaptic signalling between neurons; induced by repetitive stimulation.

Müller glia

Radial support cells located in the retina.

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Longo, F., Massa, S. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 12, 507–525 (2013). https://doi.org/10.1038/nrd4024

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