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Vol. 289, Issue 3, 1202-1210, June 1999
Center for Research on Occupational and Environmental Toxicology
(B.G.G., V.D., H.G.) and Department of Cell and Developmental Biology
(B.G.G.), Oregon Health Sciences University, Portland, Oregon; and
Departments of Molecular Physiology and Biophysics (W.S.) and
Pathology, Cell Biology and Molecular and Human Genetics (M.M.M.),
Baylor College of Medicine, Houston, Texas
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 
-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 -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 -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.
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