Background and purpose: Dimemorfan (a 1 receptor agonist) showed neuroprotective properties

Background and purpose: Dimemorfan (a 1 receptor agonist) showed neuroprotective properties in animal models of inflammation-mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear. cell culture Our Institutional Review Board in accordance with international guidelines approved all experimental protocols performed in this study. Human neutrophils were obtained by venepuncture from adult healthy volunteers and collected into syringes made up of heparin (20?U?mL?1 blood) according to our previous report (Shen (0.5?mg?mL?1) at 550?nm and the production of uric acid at 290?nm over 5?min using a spectrophotometer (Hitachi Ltd, Tokyo, Japan). Detection of cytokine production by intracellular immunofluorescence staining The positively stained cell population (%) and intensity (MCF) of cytokine-producing microglial cells were determined PF-2341066 distributor as described (Di Francesco Student-Newman-Keuls in resting cells (823.0?nM) from each data point. Data are expressed as the means.e.m. (by showing that dimemorfan treatment decreased neutrophil infiltration and oxidative stress production induced by LPS, in the lung and liver of mice. Microglial cells are one of the most important immuno-effector cells in brain inflammatory responses which mediate neurodegeneration (Rong and Baudry, 1996; Van Eldik concentration appears to be comparable to the blood concentration of dimemorfan after the treatment used in the endotoxin shock model in mice (1C5?mg?kg?1, i.p., at three successive times). Although this dose is higher than those used in the antitussive activity of 1 1 receptor agonists in animals (Brown em et al /em ., 2004), but it was still within the safe and pharmacologically applicable dosage range. The maximum non-toxic dose in rats was 25?mg?kg?1 per day in males and 50?mg?kg?1 per day in females after 5 weeks oral administration, and 25?mg?kg?1 per day in both sexes after 26 weeks oral administration. In other species, the maximum nontoxic dose was 50?mg?kg?1 per day in male mice, 25?mg?kg?1 per day in male guinea pigs, and 10?mg?kg?1 per day in male dogs (Miki em et al /em ., 1972; Yoshida em et al /em ., 1972). Because 1 receptor agonists have been reported to have anti-inflammatory effect (Bourri em et al /em ., 2002, 2004), it is reasonable to speculate that dimemorfan should activate the 1 receptors to exhibit its anti-inflammatory effect. However, the present study demonstrated that this 1 receptor antagonist BD1047 itself had some inhibitory effect and potentiated dimemorfan’s inhibition of ROS production in neutrophils, indicating that the 1 receptors were not involved in dimemorfan’s effects. In addition, PF-2341066 distributor dextromethorphan, an analogueue of dimemorfan, has been PF-2341066 distributor reported to be beneficial in inflammation-mediated neurodegeneration through inhibition of microglial activation (Liu em et al /em ., 2003) and to prevent LPS-induced sepsis in rats by reduction in pro-inflammatory cytokine release (TNF-) and suppression of NO production, and by its antioxidant properties (Wang em et al /em ., 2004a). Although dextromethorphan is Mouse monoclonal to EPO effective in the inhibition of ROS production in neutrophils, it was less potent than dimemorfan in this study. Unlike dimemorfan, dextromethorphan is usually metabolized to dextrophan to cause phencyclidine-like behavioural side effects (Kase em et al /em ., 1976). In conclusion, our results exhibited that dimemorfan displays inhibitory activities on both ROS and NO production in inflammatory cells that allow it to be an effective anti-inflammatory drug em in vivo PF-2341066 distributor /em . The anti-inflammatory properties of dimemorfan could be due, at least in part, to limiting NOX-dependent ROS and iNOS-dependent NO production, as well as pro-inflammatory cytokine release through modulation of intracellular calcium concentration and NF-B signalling pathway in inflammatory cells. As a highly effective and widely used antitussive for more than 30.