Beneficial effects of LK-4, an analog of dextromethorphan on lipopolysaccharide-induced sepsis in rats

Abstract

SummaryDextromethorphan (DM), an anti-tussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. In our preliminary screening test, LK-4, an analog of DM, can afford more protection against circulatory failure induced by LPS than that of DM. Thus, the aim of this study was to evaluate the effects of LK-4 on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anesthetized Wistar rats and survival rate by intraperitoneal administration of LPS (70 mg/kg) in conscious ICR mice. Results demonstrated that posttreatment with LK-4 (3 and 5 mg/ kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, LK-4 (3 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-a, as well as values of GOT and GPT, and BUN and creatinine caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by LK-4. Moreover, infiltration of neutrophils into the lungs and liver of rats 8 h after treatment with LPS was also reduced by LK-4. Furthermore, LK-4 increased the survival rate of mice insulted by toxic dose of LPS. In conclusion, the beneficial effects of LK-4 on LPS-induced sepsis result from its antiinflammatory and anti-oxidant effects. Thus, LK-4 can be potentially used as a therapeutic agent for sepsis in the future.

The vignette for the V13N6 issue

“…LK-4, an analog of DM, has greater potency of anticonvulsant/neuro-protective actions than DM has [16]. Jiau et al [17] found that treatment with LK-4 significantly attenuates the deleterious hemodynamic changes in rats treated with LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS are also reduced by LK-4.…”

Anti‐inflammatory effects of dimemorfan on inflammatory cells and LPS‐induced endotoxin shock in mice

“…Therefore, we used two acute inflammation‐related cellular models: (1) activation of human neutrophils by receptor‐mediated (for example, N ‐formyl‐methionyl‐leucyl‐phenylalanine; fMLP) and non‐receptor‐mediated (for example, phorbol‐12‐myristate‐13‐acetate; PMA) induction of ROS production and Mac‐1 (CD11b/CD18) upregulation, and (2) LPS‐induced production of NO, ROS, and pro‐inflammatory cytokines, as well as iNOS expression and NF‐κB signalling in the murine microglial cell line, BV2, to evaluate the anti‐inflammatory effects of dimemorfan and the possible mechanisms of its actions in this study. Furthermore, LPS‐induced endotoxin shock in mice, a model of systemic inflammation ( Jiau et al ., 2006 ), was used to examine the in vivo activity of dimemorfan. Our results demonstrated that dimemorfan exhibits anti‐inflammatory properties through σ 1 ‐receptor independent mechanism(s) by inhibiting the production of NOX‐dependent ROS and iNOS‐dependent NO, as well as that of pro‐inflammatory cytokines, probably via modulation of NF‐κB signalling in activated inflammatory cells.…”

Anti‐inflammatory effects of dimemorfan on inflammatory cells and LPS‐induced endotoxin shock in mice

“…Therefore, we used two acute inflammation-related cellular models: (1) activation of human neutrophils by receptor-mediated (for example, N-formyl-methionyl-leucyl-phenylalanine; fMLP) and non-receptor-mediated (for example, phorbol-12myristate-13-acetate; PMA) induction of ROS production and Mac-1 (CD11b/CD18) upregulation, and (2) LPS-induced production of NO, ROS, and pro-inflammatory cytokines, as well as iNOS expression and NF-kB signalling in the murine microglial cell line, BV2, to evaluate the anti-inflammatory effects of dimemorfan and the possible mechanisms of its actions in this study. Furthermore, LPS-induced endotoxin shock in mice, a model of systemic inflammation (Jiau et al, 2006), was used to examine the in vivo activity of dimemorfan. Our results demonstrated that dimemorfan exhibits anti-inflammatory properties through s 1 -receptor independent mechanism(s) by inhibiting the production of NOXdependent ROS and iNOS-dependent NO, as well as that of pro-inflammatory cytokines, probably via modulation of NF-kB signalling in activated inflammatory cells.…”