Transient Receptor Potential Vanilloid 1 Agonists as Candidates for Anti-inflammatory and Immunomodulatory Agents Export

@article{citeulike:6052074, abstract = {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-α 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-α and interleukin (IL)-1β production while augmenting IL-10 production in mice. It also inhibited TNF-α and IL-1β 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-α production. These results suggest that the TPPV1 agonistic effects inhibit TNF-α 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-α, IL-1β, IL-12p40, IL-17, and interferon (IFN)-γ, 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.}, author = {Tsuji, Fumio and Murai, Masaaki and Oki, Kenji and Seki, Iwao and Ueda, Kenji and Inoue, Hiroyuki and Nagelkerken, Lex and Sasano, Minoru and Aono, Hiroyuki}, citeulike-article-id = {6052074}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.ejphar.2009.10.044}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0014299909009510}, day = {28}, doi = {10.1016/j.ejphar.2009.10.044}, issn = {00142999}, journal = {European Journal of Pharmacology}, month = {October}, posted-at = {2009-10-31 23:05:51}, title = {Transient Receptor Potential Vanilloid 1 Agonists as Candidates for Anti-inflammatory and Immunomodulatory Agents}, url = {http://dx.doi.org/10.1016/j.ejphar.2009.10.044}, year = {2009} }

TY - JOUR ID - citeulike:6052074 L3 - citeulike-article-id:6052074 N2 - 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-α 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-α and interleukin (IL)-1β production while augmenting IL-10 production in mice. It also inhibited TNF-α and IL-1β 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-α production. These results suggest that the TPPV1 agonistic effects inhibit TNF-α 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-α, IL-1β, IL-12p40, IL-17, and interferon (IFN)-γ, 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. JF - European Journal of Pharmacology SN - 00142999 TI - Transient Receptor Potential Vanilloid 1 Agonists as Candidates for Anti-inflammatory and Immunomodulatory Agents AU - Tsuji, Fumio AU - Murai, Masaaki AU - Oki, Kenji AU - Seki, Iwao AU - Ueda, Kenji AU - Inoue, Hiroyuki AU - Nagelkerken, Lex AU - Sasano, Minoru AU - Aono, Hiroyuki PY - 2009/10/28/ UR - http://dx.doi.org/10.1016/j.ejphar.2009.10.044 ER -