European journal of pharmacology
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Ulcerative colitis is an autoimmune-inflammatory disease characterized by abnormally increased expression of Toll-like receptor-4 (TLR4) in colonic epithelial cells, increased production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta, IL-6, IL-12), chemokines (e.g., IP-10), and endothelial cell adhesion molecules (e.g., VCAM-1), plus enhanced leukocyte infiltration into colonic interstitium. Previously, we have shown that phenyl methimazole (C10) markedly decreases virally-induced TLR-3 expression and signaling and potently inhibits both TNF-alpha-induced VCAM-1 expression and the resultant leukocyte-endothelial cell adhesion. In this study we probed the hypothesis that C10 is efficacious in a TLR-4- and VCAM-1-associated murine model [the dextran sulfate sodium (DSS) model] of human colitis. ⋯ Northern blot analyses and immunohistochemistry of colonic tissue revealed that C10 markedly diminished DSS-induced expression of pertinent inflammatory mediators: TNF-alpha, IL-1beta, IL-6, IL-12, IP-10, TLR-4 and VCAM-1. Most importantly, C10 significantly improved survival and protected mice against DSS-induced colitic-death: 75% by comparison to 12.5% with identical treatment with DMSO-control (log rank test: P=0.005). These results provide direct evidence that C10 suppresses DSS-induced colitis by inhibiting expression of key inflammatory mediators and leukocyte infiltration, and is a potentially attractive therapeutic for colitis.
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Pregabalin, a ligand of alpha(2)delta subunits of voltage-gated calcium channels, reduces visceral hypersensitivity associated with irritable bowel syndrome. However, effects of pregabalin on bowel function are not well described. We investigated the effects of pregabalin on bowel dysfunction and colonic nociceptive threshold in sensitized rats. ⋯ Moreover, pregabalin was more potent in reducing disturbed defecation compared with reduction in nociceptive threshold to distension in TNBS-sensitized rats. This is the first report that pregabalin modulates stress-induced defecation in rats. These data indicate that pregabalin can ameliorate both altered defecation and decreases in colonic nociceptive threshold, suggesting that pregabalin might warrant investigation for the treatment of irritable bowel syndrome.
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Arvanil is a metabolically stable hybrid between anandamide and capsaicin. The present study was designed to test the role of the vagal pathway in post-arvanil respiratory and blood pressure responses. Respiratory and pressure changes evoked by an intravenous injection of arvanil were investigated in 21 urethane-chloralose anaesthetised and spontaneously breathing rats. ⋯ Arvanil-induced increase in mean arterial blood pressure still persisted after supranodose vagotomy. Results indicated that the respiratory effects evoked by arvanil administered via the peripheral circulation require intact midcervical vagi. Supranodose vagotomy failed to eliminate the hypertension evoked by arvanil.
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Comparative Study
Pungency of TRPV1 agonists is directly correlated with kinetics of receptor activation and lipophilicity.
TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. ⋯ We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.
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Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis. It has multiple pharmacological effects, notably as an anti-oxidant. The aim of this study was to evaluate the effects of magnolol on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anaesthetized Wistar rats. ⋯ The induction of inducible nitrous oxide (NO) synthase and the overproduction of NO and superoxide anions by LPS were also significantly reduced by post-treatment with magnolol. Moreover, the plasma level of the thrombin-antithrombin complex following administration of LPS was also reduced by post-treatment with magnolol. Thus, the beneficial effects of magnolol on LPS-induced sepsis result from its anti-inflammatory, anti-coagulatory, and anti-oxidant effects.