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FK1706, a novel non-immunosuppressive immunophilin: neurotrophic activity and mechanism of action
- Source :
-
European Journal of Pharmacology . Feb2005, Vol. 509 Issue 1, p11-19. 9p. - Publication Year :
- 2005
-
Abstract
- Abstract: Immunophilin ligands are neuroregenerative agents, characterized by binding to FK506 binding proteins (FKBPs), which stimulate recovery of neurons in a variety of injury paradigms. Here we report the discovery of a novel, non-immunosuppressive immunophilin ligand, FK1706. FK1706, a derivative of FK506, showed similarly high affinity for two FKBP subtypes, FKBP-12 and FKBP-52, but inhibited T-cell proliferation and interleukin-2 cytokine production with much lower potency and efficacy than FK506. FK1706 (0.1 to 10 nM) significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in SH-SY5Y cells, as did FK506. This neurite potentiation could be blocked by an anti-FKBP-52 antibody, as well as by specific pharmacological inhibitors of phospholipase C (PLC), phosphatidylinositol 3-kinase (PI3K), and the Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) signaling pathway. FK1706 also potentiated NGF-induced MAPK activation, with a similar dose-dependency to that necessary for potentiating neurite outgrowth. Taken together, these data suggest that FK1706 is a non-immunosuppressive immunophilin ligand with significant neurotrophic effects, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway, and therefore that FK1706 may have therapeutic potential in a variety of neurological disorders. [Copyright &y& Elsevier]
- Subjects :
- *CARRIER proteins
*NERVOUS system
*NERVE growth factor
*T cells
Subjects
Details
- Language :
- English
- ISSN :
- 00142999
- Volume :
- 509
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17411680
- Full Text :
- https://doi.org/10.1016/j.ejphar.2004.12.023