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 hippocamp al 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 pre vented by the addition of a monoclonal antibody (50-100 nM) to the immunoph ilin 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 al so neurotrophic. The neurotrophic activity of dexamethasone (50 nM) is pote ntiated by FK506, whereas that of beta-estradiol (50 nM) is not altered, su ggesting a common mechanisms of action. Geldanamycin (which disrupts mature steroid receptor complexes) is also neurotrophic (0.1-10 nM), whereas it r educes the neurotrophic activity of FK506 and steroid hormones (dexamethaso ne and beta-estradiol). Conversely, 20 mM molybdate (which prevents the dis ruption of mature steroid receptor complexes) decreases the neurotrophic ac tivity of FK506, FKBP-52 antibody, dexamethasone, and beta-estradiol. In ra ts, FK506 (10 mg/kg s.c.) augments the regenerative response of regeneratin g motor and sensory neurons to nerve injury as shown by its ability to incr ease 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 repre sent novel targets for the rational design of new neurotrophic drugs.