FK1706, a novel non-immunosuppressive immunophilin ligand, modifies the course of painful diabetic neuropathy

FK1706, a derivative of FK506, is a non-immunosuppressive immunophilin ligand with significant neurotrophic activity mediated via FKBP-52 and the RAS/RAF/MAPK signaling pathway. Here, we tested the effect of FK1706 on painful diabetic neuropathy in rat model of diabetes induced by streptozotocin (ST...

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Bibliographic Details
Published in:Neuropharmacology 2008-12, Vol.55 (7), p.1226-1230
Main Authors: Yamazaki, Shunji, Yamaji, Takayuki, Murai, Nobuhito, Yamamoto, Hiroko, Price, Raymond D., Matsuoka, Nobuya, Mutoh, Seitaro
Format: Article
Language:English
Subjects:
Allodynia
Amines - pharmacology
Analgesics - pharmacology
Animals
Cyclohexanecarboxylic Acids - pharmacology
Diabetes Mellitus, Experimental - complications
Diabetic Neuropathies - drug therapy
Diabetic Neuropathies - psychology
Diabetic neuropathy
Dose-Response Relationship, Drug
FK1706
Gabapentin
gamma-Aminobutyric Acid - pharmacology
Immunohistochemistry
Immunophilin
Immunophilins - chemistry
Ligands
Male
Nerve fiber
Pain
Pain - drug therapy
Pain - etiology
Pain Measurement - drug effects
Physical Stimulation
Rats
Rats, Sprague-Dawley
Tacrolimus - analogs & derivatives
Tacrolimus - pharmacology
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Summary:FK1706, a derivative of FK506, is a non-immunosuppressive immunophilin ligand with significant neurotrophic activity mediated via FKBP-52 and the RAS/RAF/MAPK signaling pathway. Here, we tested the effect of FK1706 on painful diabetic neuropathy in rat model of diabetes induced by streptozotocin (STZ). FK1706 ameliorated mechanical allodynia in this model at doses over 0.32 mg/kg, p.o., even if treatment was initiated after neuropathy was established, and did not affect plasma glucose levels. Furthermore, this improvement continued at least 4 weeks after the last administration. In morphological analysis, FK1706 treatment also restored intraepidermal nerve fiber density in footpad skin to almost normal levels. Gabapentin also improved mechanical allodynia in the same model, but efficacy disappeared the day after administration stopped. Allodynia responses were potentiated by co-administration of both compounds. Thus, FK1706 ameliorated painful diabetic neuropathy via a different mechanism from gabapentin and improved morphological outcomes, indicating that FK1706 improves painful diabetic neuropathy by modifying the underlying disease pathology.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2008.07.048