Does Timocor promote neurite outgrowth?
Or, does small molecule ligand which bind to FKBP-12 actually also bind to PKBP-52 (new ligand for FK506) and enhance wonted effects?
Drug Metab Rev 1999 Aug;31(3):649-63
FK506 and the role of the immunophilin FKBP-52 in nerve regeneration.
Gold BG
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201, USA.
In summary, FKBP-12 does not mediate the neurite outgrowth-promoting properties of neuroimmunophilin ligands (e.g., FK506). Instead, the neurotrophic properties of neuroimmunophilin ligands (FK506) and steroid hormones are mediated by disruption of steroid-receptor complexes. It remains unclear which component mediates neurite outgrowth, although the most likely candidates are FKBP-52, hsp-90, and p23 [42]. Regardless of the underlying mechanism involved, the FKBP-52 antibody data reveal that it should be possible to design, based on the structure of FK506, non-FKBP-12-binding (nonimmunosuppressant) compounds selective for FKBP-52 and test these new libraries for their ability to augment nerve regeneration. It may also be possible to exploit the structure of geldanamycin to develop a new class of hsp-90-binding compounds for use in nerve regeneration.
J Pharmacol Exp Ther 1999 Jun;289(3):1202-10
Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506.
Gold BG, Densmore V, Shou W, Matzuk MM, Gordon HS
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland, Oregon. gold@ohsu.edu
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.
Mol Neurobiol 1997 Dec;15(3):285-306
FK506 and the role of immunophilins in nerve regeneration.
Gold BG
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201, USA.
FK506 is a new FDA-approved immunosuppressant used for prevention of allograft rejection in, for example, liver and kidney transplantations. FK506 is inactive by itself and requires binding to an FK506 binding protein-12 (FKBP-12), or immunophilin, for activation. In this regard, FK506 is analogous to cyclosporin A, which must bind to its immunophilin (cyclophilin A) to display activity. This FK506-FKBP complex inhibits the activity of the serine/threonine protein phosphatase 2B (calcineurin), the basis for the immunosuppressant action of FK506. The discovery that immunophilins are also present in the nervous system introduces a new level of complexity in the regulation of neuronal function. Two important calcineurin targets in brain are the growth-associated protein GAP-43 and nitric oxide (NO) synthase (NOS). This review focuses on studies showing that systemic administration of FK506 dose-dependently speeds nerve regeneration and functional recovery in rats following a sciatic-nerve crush injury. The effect appears to result from an increased rate of axonal regeneration. The nerve regenerative property of this class of agents is separate from their immunosuppressant action because FK506-related compounds that bind to FKBP-12 but do not inhibit calcineurin are also able to increase nerve regeneration. Thus, FK506's ability to increase nerve regeneration arises via a calcineurin-independent mechanism (i.e., one not involving an increase in GAP-43 phosphorylation). Possible mechanisms of action are discussed in relation to known actions of FKBPs: the interaction of FKBP-12 with two Ca2+ release-channels (the ryanodine and inositol 1,4,5-triphosphate receptors) which is disrupted by FK506, thereby increasing Ca2+ flux; the type 1 receptor for the transforming growth factor-beta (TGF-beta 1), which stimulates nerve growth factor (NGF) synthesis by glial cells, and is a natural ligand for FKBP-12; and the immunophilin FKBP-52/FKBP-59, which has also been identified as a heat-shock protein (HSP-56) and is a component of the nontransformed glucocorticoid receptor. Taken together, studies of FK506 indicate broad functional roles for the immunophilins in the nervous system. Both calcineurin-dependent (e.g., neuroprotection via reduced NO formation) and calcineurin-independent mechanisms (i.e., nerve regeneration) need to be invoked to explain the many different neuronal effects of FK506. This suggests that multiple immunophilins mediate FK506's neuronal effects. Novel, nonimmunosuppressant ligands for FKBPs may represent important new drugs for the treatment of a variety of neurological disorders.
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