Non-FK506-binding protein-12 neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration

Authors

  • Bruce G. Gold,

    Corresponding author
    1. Department of Neurology, Oregon Health and Science University, Portland, Oregon
    2. Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon
    3. Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon
    • Department of Neurology/L606, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098
    Search for more papers by this author
  • David M. Armistead,

    1. Oxford Bioscience Partners, Boston, Massachusetts
    Search for more papers by this author
  • Min-Sheng Wang

    1. Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon
    Current affiliation:
    1. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
    Search for more papers by this author

Abstract

Neurotrophic activity of neuroimmunophilin ligands (FK506 and its nonimmunosuppressant derivatives) has been assumed to be mediated by the FK506-binding protein-12 (FKBP-12). We recently showed that activity is retained in hippocampal neurons from FKBP-12 knockout mice, indicating that binding to FKBP-12 is not necessary. Here we show that three nonimmunosuppressant FK506 derivatives (V-13,450, V-13,629, and V-13,670) that do not bind FKBP-12 (>12.5 mM affinity) are equipotent to FKBP-12 ligands (FK506, V-10,367, and V-13,449) for increasing neurite elongation in SH-SY5Y cells. One non-FKBP-12 ligand (V-13,670) is also shown to accelerate functional recovery and nerve regeneration in the rat sciatic nerve crush model. Surprisingly, it exhibited an unusual dose-response effect upon oral administration, showing a novel bimodal dose-response for behavioral functional recovery and myelination, but not for axonal size, suggesting both Schwann cell and neuronal targets. Orally active non-FKBP-12 neuroimmunophilin ligands may be useful for the treatment of human neurological disorders without any potential side effects resulting from FKBP-12 binding. © 2005 Wiley-Liss, Inc.

Ancillary