morphinans and Shock--Septic

Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Proliferation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Morphinans; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Shock, Septic; Signal Transduction; Tumor Necrosis Factor-alpha

Dimemorfan (a sigma1 receptor agonist) showed neuroprotective properties in animal models of inflammation-mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear.. The effects of dimemorfan on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)- induced neutrophils and lipopolysaccharide (LPS)-activated microglial cells, as well as LPS-induced endotoxin shock in mice were elucidated.. Dimemorfan decreased PMA- and fMLP-induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of sigma1 receptors, possibly by blocking ROS production and G-protein-mediated intracellular calcium increase. Dimemorfan also inhibited LPS-induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha (TNF-alpha), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up-regulation through interfering with nuclear factor kappa-B (NF-kappaB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg(-1), i.p., at three successive times after LPS) decreased plasma TNF-alpha, and neutrophil infiltration and oxidative stress in the lung and liver.. Our results suggest that dimemorfan acts via sigma1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kappaB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro-inflammatory cytokines. These effects may contribute its anti-inflammatory action and protective effects against endotoxin shock in mice.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Calcium; Cytokines; Fluorescent Antibody Technique; Humans; I-kappa B Proteins; Inflammation; Lipopolysaccharides; Macrophage-1 Antigen; Mice; Morphinans; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Reactive Oxygen Species; Shock, Septic; Tetradecanoylphorbol Acetate; Transcription Factor RelA; Up-Regulation

Topics: Aged; Aged, 80 and over; Anesthesia, Intravenous; Butorphanol; Female; Hemodynamics; Humans; Male; Middle Aged; Morphinans; Shock, Septic