Neuroimmunophilin ligands: the development of novel neuroregenerative/ neuroprotective compounds.
FK506 (tacrolimus), initially developed as an immunosuppressant drug, represents a class of compounds with potential high impact for the treatment of human neurological disorders. While immunosuppression is mediated by the 12-kD FK506-binding-protein (FKBP-12), the neurite elongation activity of FK506 involves FKBP-52 (also known as FKBP-59 or Hsp-56), a component of mature steroid receptor complexes: FKBP-52 binds to Hsp-90, which bind to p23 and the steroid receptor protein to form the complex. The brief review focuses on how three classes of compounds (FK506 derivatives, steroid hormones, and ansamycin anti-cancer drugs, e.g., geldanamycin) increase neurite elongation/nerve regeneration (axonal elongation). A model is presented whereby neurite elongation is elicited by compounds that bind to steroid receptor chaperone proteins (e.g., FKBP-52 and Hsp-90) and thereby disrupt mature steroid receptor complexes (comprising FKBP-52, Hsp-90 and p23 in addition to the steroid receptor binding protein). Disruption of the complex leads to a "gain-of-function" whereby one or more of these steroid receptor chaperone proteins (i.e, FKBP-52, Hsp-90 or p23) activates mitogen-associated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) pathway. Thus, the neurotrophic actions of these distinct classes of compounds can be understood from their ability to bind steroid receptor chaperones, thereby providing a unique receptor-mediated means to activate the ERK pathway. These studies thereby shed new light on the intrinsic mechanism regulating axonal elongation. Furthermore, this mechanism may also underlie calcineurin-independent neuroprotective actions of FK506. We suggest that components of steroid receptor complexes are novel targets for the design of neuroregenerative/neuroprotective drugs.
Gold
Bruce G
BG
Center for Research on Occupational and Environmental Toxicology, Developmental Biology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201-3098, USA. gold@ohsu.edu
Villafranca
J Ernest
JE
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D006801:Humans; D020104:Immunophilins / Q000627:therapeutic use; D008024:Ligands; D009416:Nerve Regeneration / Q000502:physiology*; D009422:Nervous System Diseases / Q000188:drug therapy*; D015398:Signal Transduction; D016559:Tacrolimus / Q000737:chemistry / Q000627:therapeutic use*
D008024:Ligands; D016572:Cyclosporine; D020104:Immunophilins; D016559:Tacrolimus