Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production.

Quercetin (1) is known to have both antioxidant and antinociceptive effects. However, the mechanism involved in its antinociceptive effect is not fully elucidated. Cytokines and reactive oxygen species have been implicated in the cascade of events resulting in inflammatory pain. Therefore, we evaluated the antinociceptive mechanism of 1 focusing on the role of cytokines and oxidative stress. Intraperitoneal and oral treatments with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid and phenyl-p-benzoquinone and also the second phase of formalin- and carrageenin-induced mechanical hypernociception. Compound 1 also inhibited the hypernociception induced by cytokines (e.g., TNFalpha and CXCL1), but not by inflammatory mediators that directly sensitize the nociceptor such as PGE2 and dopamine. On the other hand, 1 reduced carrageenin-induced IL-1beta production as well as carrageenin-induced decrease of reduced glutathione (GSH) levels. These results suggest that 1 exerts its analgesic effect by inhibiting pro-nociceptive cytokine production and the oxidative imbalance mediation of inflammatory pain.

Role of cytokines in mediating mechanical hypernociception in a model of delayed-type hypersensitivity in mice.

In the present study, we used the electronic version of the von Frey test to investigate the role of cytokines (TNF-alpha and IL-1beta) and chemokines (KC/CXCL-1) in the genesis of mechanical hypernociception during antigen-induced inflammation in mice. The nociceptive test consisted of evoking a hindpaw flexion reflex with a hand-held force transducer (electronic anesthesiometer) adapted with a 0.5 mm(2) polypropylene tip. The intraplantar administration of methylated bovine serum albumin (mBSA) in previously immunized (IM), but not in sham-immunized (SI) mice, induced mechanical hypernociception in a dose-dependent manner. Hypernociception induced by antigen was reduced in animals pretreated with IL-1ra and reparixin (a non-competitive allosteric inhibitor of CXCR2), and in TNF receptor type 1 deficient (TNFR1-/-) mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1beta and KC/CXCL-1 in IM, but not in SI, mice. The increase in TNF-alpha levels preceded the increase in IL-1beta and KC/CXCL1. Antigen-induced release of IL-1beta and KC/CXCL1 was reduced in TNFR1-/- mice, and TNF-alpha-induced hypernociception was inhibited by IL-1ra and reparixin. Hypernociception induced by IL-1beta in immunized mice was inhibited by indomethacin, whereas KC/CXCL1-induced hypernociception was inhibited by indomethacin and guanethidine. Antigen-induced hypernociception was reduced by indomethacin and guanethidine and abolished by the two drugs combined. Together, these results suggest that inflammation associated with an adaptive immune response induces hypernociception that is mediated by an initial release of TNF-alpha, which triggers the subsequent release of IL-1beta and KC/CXCL1. The latter cytokines in turn stimulate the release of the direct-acting final mediators, prostanoids and sympathetic amines.

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice.

IL-33, a new member of the IL-1 family, signals through its receptor ST2 and induces T helper 2 (Th2) cytokine synthesis and mediates inflammatory response. We have investigated the role of IL-33 in antigen-induced hypernociception. Recombinant IL-33 induced cutaneous and articular mechanical hypernociception in a time- and dose-dependent manner. The hypernociception was inhibited by soluble (s) ST2 (a decoy receptor of IL-33), IL-1 receptor antagonist (IL-1ra), bosentan [a dual endothelin (ET)(A)/ET(B) receptor antagonist], clazosentan (an ET(A) receptor antagonist), or indomethacin (a cyclooxygenase inhibitor). IL-33 induced hypernociception in IL-18(-/-) mice but not in TNFR1(-/-) or IFNgamma(-/-) mice. The IL-33-induced hypernociception was not affected by blocking IL-15 or sympathetic amines (guanethidine). Furthermore, methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception depended on TNFR1 and IFNgamma and was blocked by sST2, IL-1ra, bosentan, clazosentan, and indomethacin. mBSA also induced significant IL-33 and ST2 mRNA expression. Importantly, we showed that mBSA induced hypernociception via the IL-33 --> TNFalpha --> IL-1beta --> IFNgamma --> ET-1 --> PGE(2) signaling cascade. These results therefore demonstrate that IL-33 is a key mediator of immune inflammatory hypernociception normally associated with a Th1 type of response, revealing a hitherto unrecognized function of IL-33 in a key immune pharmacological pathway that may be amenable to therapeutic intervention.

Exposição ambiental a desreguladores endócrinos: alterações na homeostase dos hormônios esteroidais e tireoideanos / Environmental exposure to endocrine disrupters: alterations in steroidal and thyroid hormones homeostasis

Endocrine disruptors, exogenous compounds that alter the endogenous hormone homeostasis, have been systematically discharged in the environment during the last 60 years. These contaminants have been related to the decrease of human sperm number and increased of the incidence of testicular, breast and thyroid cancer. During the same period, developmental and reproductive effects have also been documented in wildlife species. This work presents a review of the effects and mechanisms of action of steroidal and thyroid disruptors. Several studies from 1950 until 2008 were reviewed in PubMed, ScienceDirect databases and text books. Our findings showed that endocrine disruptors can act by the following mechanisms: i) inhibition of enzymes related to hormone synthesis; ii) alteration of free concentration of hormones by interaction with plasmatic globulins; iii) alteration in expression of hormone metabolism enzymes; iv) interaction with hormone receptors, acting as agonists or antagonists; v) alteration of signal transduction resulting from hormone action. The importance of the identification of endocrine disruptors involves characterization of environmental contaminants and inquiry of new substances discharged in the environment. The minimization of exposure and/or rationalization of the use of these compounds are related to the preservation of some species, in order to prevent extinction process.

Desreguladores endócrinos, substâncias exógenas que alteram a homeostase de hormônios endógenos, têm sido constantemente lançados no ambiente durante os últimos 60 anos. Esses contaminantes têm sido relacionados à diminuição da contagem espermática humana e ao aumento da incidência de câncer de testículo, mama e tireóide. No mesmo período, alterações no desenvolvimento e reprodução foram documentadas em espécies de animais selvagens. O objetivo do trabalho foi revisar os efeitos e mecanismos de ação dos desreguladores endócrinos que alteram a homeostase dos hormônios esteroidais e tireoideanos. Foi realizado um levantamento de artigos do período de 1950 a 2008 através das bases de dados PUBMED e ScienceDirect, além de livros da área. Os resultados mostram que os desreguladores endócrinos podem agir pelos seguintes mecanismos: i) inibição de enzimas relacionadas com a síntese de hormônios; ii) alteração da concentração livre de hormônios através da interação com globulinas plasmáticas; iii) alteração da expressão de enzimas relacionadas ao metabolismo hormonal; iv) interação com receptores hormonais, agindo como agonistas ou antagonistas; v) alteração da transdução de sinais resultante da ação hormonal. A importância da identificação dos desreguladores endócrinos envolve o estudo dos contaminantes ambientais e a investigação de novas substâncias lançadas no meio ambiente. A minimização da exposição e/ou a racionalização do uso desses compostos está relacionada a preservação de espécies, para previnir processos de extinção.

Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production-dependent mechanism.

The anti-inflammatory activities of some medicinal plants are attributed to their contents of sesquiterpene lactones. In the present study, the anti-inflammatory and anti-nociceptive activity of a sesquiterpene lactone isolated from Viguiera robusta, budlein A in mice was investigated. The treatment with budlein A dose--(1.0-10.0 mg/kg, p.o., respectively) dependently inhibited the carrageenan-induced: i. neutrophil migration to the peritoneal cavity (2-52%), ii. neutrophil migration to the paw skin tissue (32-74%), iii. paw oedema (13-74%) and iv. mechanical hypernociception (2-58%) as well as the acetic acid-induced writhings (0-66%). Additionally, budlein A (10.0 mg/kg) treatment inhibited the mechanical hypernociception-induced by tumour necrosis factor (TNF-alpha, 36%), Keratinocyte-derived chemokine (KC, 37%) and Interleukin-1beta (IL-1beta, 28%), but not of prostaglandin E(2) or dopamine. Budlein A also inhibited the carrageenan-induced release of TNF-alpha (52%), KC (70%) and IL-1beta (59%). Furthermore, an 8 days treatment with budlein A inhibited Complete Freund's adjuvant (10 microl/paw)-induced hypernociception, paw oedema and paw skin myeloperoxidase activity increase while not affecting the motor performance or myeloperoxidase activity in the stomach. Concluding, the present data suggest that budlein A presents anti-inflammatory and antinociceptive property in mice by a mechanism dependent on inhibition of cytokines production. It supports the potential beneficial effect of orally administered budlein A in inflammatory diseases involving cytokine-mediated nociception, oedema and neutrophil migration.