FK1706, a novel non-immunosuppressive immunophilin: neurotrophic activity and mechanism of action.
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.
Price
Raymond D
RD
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Yamaji
Takayuki
T
Yamamoto
Hiroko
H
Higashi
Yasuyuki
Y
Hanaoka
Kaori
K
Yamazaki
Shunji
S
Ishiye
Masayuki
M
Aramori
Ichiro
I
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
Yanagihara
Takehiko
T
Gold
Bruce G
BG
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D020104:Immunophilins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D009414:Nerve Growth Factors; D014316:Tritium; D020813:Receptor, trkB; D020928:Mitogen-Activated Protein Kinases; D022061:Tacrolimus Binding Protein 1A; D020104:Immunophilins; C505380:FK1706; D016559:Tacrolimus