Toxin-Induced Death of Neurotrophin-Sensitive Neurons

  • Ronald G. Wiley
Part of the Methods in Molecular Biology™ book series (MIMB, volume 169)


Selective destruction of neurons based on the use of targeted toxins has proven successful for several types of neurons (1). This chapter will describe the use of an immunotoxin to selectively destroy rat neurons that express the low-affinity neurotrophin receptor (p75NTR) (2). This immunotoxin consists of a monoclonal antibody disulfide coupled to a ribosome inactivating protein. The most extensively used and studied version uses the antibody 192 IgG originally developed as an antibody to a rat NGF-binding protein (3). 192 IgG has been extensively used to study rat p75NTR. Results of these studies have demonstrated p75NTR expression on a variety of neurotrophin-responsive cells, including sympathetic ganglion neurons, some primary sensory neurons, and cholinergic neurons of the basal forebrain. p75NTR also is expressed on cells not known to be responsive to neurotrophins, such as cerebellar Purkinje neurons and numerous other tissues during development (4). Thus, producing selective lesions using 192 IgG also requires restricting application of the immunotoxin to the region of the target cells.


Cholinergic Neuron Basal Forebrain Cresyl Violet Primary Sensory Neuron Medial Septum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Wiley, R. G. and Lappi, D. A. (1994) Suicide transport and immunolesioning. R.G. Landes Co., Austin, TX.Google Scholar
  2. 2.
    Wiley, R. G., Oeltmann, T. N., and Lappi, D. A. (1991) Immunolesioning: selective destruction of neurons using immunotoxin to rat NGF receptor. Brain Res. 562, 149–153.PubMedCrossRefGoogle Scholar
  3. 3.
    Chandler, C. E., Parsons, L. M., Hosang, M., and Shooter, E. M. (1984) A monoclonal antibody modulates the interaction of nerve growth factor with PC 12 cells. J. Biol. Chem. 259, 6882–6889.PubMedGoogle Scholar
  4. 4.
    Cuello, A. C., Pioro, E. P., and Ribeiro-da-Silva, A. (1990) Cellular and subcellular localization of nerve growth factor receptor-like immunoreactivity in the rat CNS. Neurochem. Int. 17, 205–213.CrossRefGoogle Scholar
  5. 5.
    Endo, Y., Mitsui, K., Motizuki, M., and Tsurugi, K. (1987) The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. J. Biol. Chem. 262, 5908–5912.PubMedGoogle Scholar
  6. 6.
    Eiklid, K., Olsnes, S., and Pihl, A. (1980) Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp. Cell Res. 126, 321–326.PubMedCrossRefGoogle Scholar
  7. 7.
    Wiley, R. G. (1992) Neural lesioning with ribosome-inactivating proteins: suicide transport and immunolesioning. Trends Neurosci. 15, 285–290.PubMedCrossRefGoogle Scholar
  8. 8.
    Siegall, C. B., Wolff, E. A., Gawlak, S. L., Paul, L., Chace, D., and Mixan, B. (1995) Immunotoxins as cancer chemotherapeutic agents. Drug Dev. Res. 34, 210–219.CrossRefGoogle Scholar
  9. 9.
    Lappi, D. A., Esch, F. S., Barbieri, L., Stirpe, F., and Soria, M. (1985) Characterization of a Saponaria officinalis seed ribosome-inactivating protein: immunoreactivity and sequence homologies. Biochem. Biophys. Res. Commun. 129, 934–942.PubMedCrossRefGoogle Scholar
  10. 10.
    Wiley, R. G. (1997) Findings about the cholinergic basal forebrain using immunotoxin to the nerve growth factor receptor. Ann. NY Ac ad. Sci. 835, 20–29.CrossRefGoogle Scholar
  11. 11.
    Wiley, R. G. and Lappi, D. A. (1997) Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin in rats. Neurosci. Lett. 230, 97–100.PubMedCrossRefGoogle Scholar
  12. 12.
    Mantyh, P. W., Rogers, S. D., Honore, P., Allen, B. J., Ghilardi, J. R., Li, J., et al. (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278, 275–279.PubMedCrossRefGoogle Scholar
  13. 13.
    Shiosaka, S. (1992) Attempts to make models for Alzheimer’s disease. Neurosci. Res. 13, 237–255.PubMedCrossRefGoogle Scholar
  14. 14.
    DiStefano, P. S., Schweitzer, J. B., Taniuchi, M., and Johnson, E. M., Jr. (1985) Selective destruction of nerve growth factor receptor-bearing cells in vitro using a hybrid toxin composed of ricin A chain and a monoclonal antibody against the nerve growth factor receptor. J. Cell Biol. 101, 1107–1114.PubMedCrossRefGoogle Scholar
  15. 15.
    Schweitzer, J. B. (1987) Nerve growth factor receptor-mediated transport from cerebrospinal fluid to basal forebrain neurons. Brain Res. 423, 309–317.PubMedCrossRefGoogle Scholar
  16. 16.
    Schweitzer, J. B. (1989) Nerve growth factor receptor-mediated transport from CSF labels cholinergic neurons: direct demonstration by a double-labeling study. Brain Res. 490, 390–396.PubMedCrossRefGoogle Scholar
  17. 17.
    Thorpe, P. E., Brown, A. N. F., Bremner, J. A. G., Foxwell, B. M. J., and Stirpe, F. (1985) An immunotoxin composed of monoclonal anti-Thy 1.1 antibody and a ribosome-inactivating protein from Saponaria officinalis: potent antitumor effects in vitro and in vivo. J. Natl. Cancer Inst. 75, 151–159.PubMedGoogle Scholar
  18. 18.
    Wiley, R. G. and Lappi, D. A. (1993) Preparation of anti-neuronal immunotoxins for selective neural immunolesioning. Neurosci. Protocols(93-0202), 1–11.Google Scholar
  19. 19.
    Heckers, S., Ohtake, T., Wiley, R. G., Lappi, D. A., Geula, C., and Mesulam, M. M. (1994) Complete and selective cholinergic denervation of rat neocortex and hippocampus but not amygdala by an immunotoxin against the p75 NGF receptor. J. Neurosci. 14, 1271–1289.Google Scholar
  20. 20.
    Greeson, D. M., Moix, L., Meier, M., Armstrong, D. M., and Wiley, R. G. (1992) A continuing signal maintains NGF receptor expression in hypoglossal motor neurons after crush injury. Brain Res. 594, 351–355.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee, M. G., Chrobak, J. J., Sik, A., Wiley, R. G., and Buzsáki, G. (1994) Hippoc-ampal theta activity following selective lesion of the septal cholinergic system. Neuroscience 62, 1033–1047.PubMedCrossRefGoogle Scholar
  22. 22.
    Harrison, M. B., Roberts, R. C., and Wiley, R. G. (1993) A selective lesion of striatonigral neurons decreases presynaptic binding of [3H]hemicholinium-3 to striatal interneurons. Brain Res. 630, 169–177.PubMedCrossRefGoogle Scholar
  23. 23.
    Book, A. A., Wiley, R. G., and Schweitzer, J. B. (1995) 192 IgG-saporin. 2. Neuropathology in the rat brain. Acta Neuropathol. (Berl.) 89, 519–526.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2001

Authors and Affiliations

  • Ronald G. Wiley
    • 1
  1. 1.Department of Neurology and PharmacologyVanderbilt University and Neurology ServiceNashville

Personalised recommendations