Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506.
The neurotrophic property of the immunosuppressant drug FK506 (tacrolimus) is believed to depend on the 12-kDa FK506-binding protein (FKBP-12). Here, we show that FK506 maintains its neurotrophic activity in primary hippocampal cell cultures from FKBP-12 knockout mice. In human neuroblastoma SH-SY5Y cells, the neurotrophic action of FK506 (10 pM to 10 nM) is completely prevented by the addition of a monoclonal antibody (50-100 nM) to the immunophilin FKBP-52 (also known as FKBP-59 or heat shock protein 56), a component of mature steroid receptor complexes. By itself, the FKBP-52 antibody is also neurotrophic. The neurotrophic activity of dexamethasone (50 nM) is potentiated by FK506, whereas that of beta-estradiol (50 nM) is not altered, suggesting a common mechanisms of action. Geldanamycin (which disrupts mature steroid receptor complexes) is also neurotrophic (0.1-10 nM), whereas it reduces the neurotrophic activity of FK506 and steroid hormones (dexamethasone and beta-estradiol). Conversely, 20 mM molybdate (which prevents the disruption of mature steroid receptor complexes) decreases the neurotrophic activity of FK506, FKBP-52 antibody, dexamethasone, and beta-estradiol. In rats, FK506 (10 mg/kg s.c.) augments the regenerative response of regenerating motor and sensory neurons to nerve injury as shown by its ability to increase the axotomy-induced induction of c-jun expression. A model is proposed to account for the neurotrophic action of both neuroimmunophilin ligands (FK506) and steroid hormones. Components of steroid receptor complexes represent novel targets for the rational design of new neurotrophic drugs.
Gold
B G
BG
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland, Oregon. gold@ohsu.edu
Densmore
V
V
Shou
W
W
Matzuk
M M
MM
Gordon
H S
HS
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016227:Benzoquinones; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004622:Embryo, Mammalian; D004958:Estradiol / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D020104:Immunophilins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D047029:Lactams, Macrocyclic; D051379:Mice; D018345:Mice, Knockout; D008982:Molybdenum / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
D000906:Antibodies; D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D047029:Lactams, Macrocyclic; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D016755:Proto-Oncogene Proteins c-jun; D011809:Quinones; D004958:Estradiol; D003907:Dexamethasone; D008982:Molybdenum; C024687:sodium molybdate(VI); D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D016559:Tacrolimus; C001277:geldanamycin