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標題: Anti-inflammatory effects of dimemorfan on inflammatory cells and LPS-induced endotoxin shock in mice
作者: Wang, Y.H.
Shen, Y.C.
Liao, J.F.
Li, C.H.
Chou, C.Y.
Liou, K.T.
Chou, Y.C.
關鍵字: cytokine;dimemorfan;endotoxin shock;iNOS;microglial cells;neutrophils;NF-kappa B;NO;ROS;nitric-oxide synthase;factor-kappa-b;oxygen species production;bv-2;microglial cells;human neutrophils;gene-expression;antitussive;activity;radical production;sigma-1 receptor;human-leukocytes
Project: British Journal of Pharmacology
期刊/報告no:: British Journal of Pharmacology, Volume 154, Issue 6, Page(s) 1327-1338.
Background and purpose: Dimemorfan (a sigma(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. Experimental approach: 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 LPSinduced endotoxin shock in mice were elucidated. Key results: Dimemorfan decreased PMA- and fMLP-induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of s1 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-kappa B) 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. Conclusions and implications: Our results suggest that dimemorfan acts via s1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kappa B 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.
ISSN: 0007-1188
DOI: 10.1038/bjp.2008.202
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