European journal of pharmacology
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Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. ⋯ Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
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Lobelane, a minor alkaloid of Lobelia inflata and a synthetic, des-oxy analog of lobeline, has good affinity for the vesicular monoamine transporter and the dopamine transporter. The current study examined the ability of lobelane to specifically decrease methamphetamine self-administration. Rats were trained on a fixed ratio 5 schedule of reinforcement to self-administer methamphetamine (0.05 mg/kg/infusion, i.v.) or to respond for sucrose pellets. ⋯ Locomotor activity was decreased following only the highest dose of lobelane (10 mg/kg). Across repeated pretreatments, tolerance developed to the effect of lobelane on methamphetamine self-administration, demonstrating that the ability of lobelane to specifically decrease methamphetamine self-administration is a transient effect. Thus, taken together, the results show that although lobelane interacts with the pharmacological targets believed to be responsible for its ability to decrease methamphetamine self-administration, removal of the oxygen functionalities from the lobeline molecule may have afforded a compound with an altered pharmacokinetic and/or pharmacodynamic profile.
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Mechanical ventilation can paradoxically cause acute lung injury, which is termed ventilator-induced lung injury. Neutrophil recruitment and neutrophil elastase release play a central role in the pathogenesis of ventilator-induced lung injury including cell damage, extracellular matrix degradation and alveolar-capillary hyperpermeability. We therefore speculated that neutrophil elastase inhibition ameliorates ventilator-induced lung injury. ⋯ Moreover, mechanical ventilation increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and the expression of early growth response gene-1 (Egr-1) mRNA, and these increases were also recovered by sivelestat. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed apoptotic cells mainly in alveolar epithelial cells and their numbers corresponded to histological damage. These data suggested that sivelestat could protect against ventilator-induced lung injury by suppressing apoptotic responses through mechanical stress-induced cell signaling in addition to inhibiting neutrophil chemotaxis.
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Bisphosphonates are widely used inhibitors of bone resorption. They also inhibit the growth of various cancer cells in vitro, but the clinical significance of this effect is unclear. The cancer growth inhibitory effects of nitrogen-containing bisphosphonates, (i.e. zoledronate) have been attributed to their ability to inhibit the mevalonate pathway. ⋯ The bisphosphonate-induced p38 activation signals for resistance against these drugs, by promoting progression through the G2/M-checkpoint. Of these pathways only growth inhibition is mediated via inhibition of the mevalonate pathway in MDA-MB-231 cells. Combining p38 inhibitors with bisphosphonates may result in increased anti-cancer efficacy.
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Cannabinoid CB(2) receptors have been implicated in antinociception in animal models of both acute and chronic pain. We evaluated the role both cannabinoid CB(1) and CB(2) receptors in mechanonociception in non-arthritic and arthritic rats. The antinociceptive effect of Delta(9)-tetrahydrocannabinol (Delta(9)THC) was determined in rats following administration of the cannabinoid CB(1) receptor-selective antagonist, SR141716A, the cannabinoid CB(2) receptor-selective antagonist, SR144528, or vehicle. ⋯ SR141716A significantly attenuated Delta(9)THC-induced antinociception in both the non-arthritic [AD(50) = 1.4 (0.8-2) mg/kg] and arthritic rat [AD(50) = 2.6 (1.8-3.1) mg/kg]. SR141716A or SR144528 alone did not result in a hyperalgesic effect as compared to vehicle. Our results indicate that the cannabinoid CB(2) receptor plays a critical role in cannabinoid-mediated antinociception, particularly in models of chronic inflammatory pain.