Tumor necrosis factor-alpha (
TNF-alpha) is known to play a crucial role in the pathogenesis of
rheumatoid arthritis. In the present study, we demonstrate the effects of
SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]
urea), a novel orally active inhibitor of
TNF-alpha production, in animal models, and its mechanism of action on
TNF-alpha production.
SA13353 significantly inhibited
lipopolysaccharide (LPS)-induced
TNF-alpha production in a dose-dependent manner in rats. Moreover,
SA13353 exhibited a binding affinity for the rat
vanilloid receptor and increased
neuropeptide release from the rat dorsal root ganglion neurons. However, its effects were blocked by pretreatment with the transient receptor potential vanilloid 1 (TRPV1) antagonist
capsazepine. The ability of
SA13353 and
capsaicin to inhibit LPS-induced
TNF-alpha production was eliminated by sensory
denervation or
capsazepine pretreatment in vivo. Although they inhibited LPS-induced
TNF-alpha production in mice, these effects were not observed in TRPV1 knockout mice.
SA13353 provoked the release of
neuropeptides without nerve inactivation, even when chronically administered to rats. These results suggest that
SA13353 inhibits
TNF-alpha production through activation of
capsaicin-sensitive afferent neurons mediated via TRPV1 in vivo. Post-onset treatment of
SA13353 strongly reduced the hindpaw swelling and joint destruction associated with
collagen-induced arthritis in rats. Thus,
SA13353 is expected to be a novel anti-arthritic agent with a unique mechanism of action.