Transient receptor potential vanilloid 1 agonists as candidates for anti-inflammatory and immunomodulatory agents.
We recently demonstrated that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 (TRPV1) agonist, inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons. In the present study, we investigated the effects of SA13353 on lipopolysaccharide (LPS)-induced cytokine production and a murine model of experimental autoimmune encephalomyelitis (EAE). SA13353 inhibited LPS-induced TNF-alpha and interleukin (IL)-1beta production while augmenting IL-10 production in mice. It also inhibited TNF-alpha and IL-1beta mRNA expression, and increased IL-10 mRNA expression in LPS-treated murine liver. These effects were not observed in TRPV1 KO and sensory denervated mice. Capsaicin and SA13353 increased serum neuropeptide levels, and calcitonin gene-related peptide fragment 8-37 (CGRP(8)(-)(37)), a CGRP antagonist, partially blocked the inhibitory effects of capsaicin and SA13353 on LPS-induced TNF-alpha production. These results suggest that the TPPV1 agonistic effects inhibit TNF-alpha production, at least partially, via neuropeptide release. SA13353 did not directly affect LPS-induced cytokine production in vitro using RAW264.7 macrophages, which do not express TRPV1. Therefore, we consider SA13353 to be a good tool for the investigation of the value of TRPV1 agonists for the treatment of chronic inflammation. In a murine EAE model, SA13353 attenuated clinical signs and histopathological changes. SA13353 attenuated cytokine levels, including TNF-alpha, IL-1beta, IL-12p40, IL-17, and interferon (IFN)-gamma, after proteolipid protein (PLP) immunization. In addition, SA13353 attenuated the increase of IL-17-producing cells. These results suggest that TRPV1 agonists may act as anti-inflammatory and immunomodulatory agents in vivo in certain inflammatory diseases.
Tsuji
Fumio
F
Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. ftsuji@minuet.plala.or.jp
Murai
Masaaki
M
Oki
Kenji
K
Seki
Iwao
I
Ueda
Kenji
K
Inoue
Hiroyuki
H
Nagelkerken
Lex
L
Sasano
Minoru
M
Aono
Hiroyuki
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003714:Denervation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007155:Immunologic Factors / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D011725:Pyridines / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D050916:TRPV Cation Channels / Q000819:agonists*; D014508:Urea / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use
C530925:1-(2-(1-adamantyl)ethyl)-1-pentyl-3-(3-(4-pyridyl)propyl)urea; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D009479:Neuropeptides; D010446:Peptide Fragments; D011725:Pyridines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C058636:calcitonin gene-related peptide (8-37); D014508:Urea; D015740:Calcitonin Gene-Related Peptide