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

Abstract

Background and purpose: Dimemorfan (a s 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-methionylleucyl-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 s 1 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-a), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up-regulation through interfering with nuclear factor kappa-B (NF-kB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg À1 , i.p., at three successive times after LPS) decreased plasma TNF-a, and neutrophil infiltration and oxidative stress in the lung and liver. Conclusions and implications: Our results suggest that dimemorfan acts via s 1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kB 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.

<i>Anethum graveloens</i> Flower Extracts Inhibited a Lipopolysaccharide-Induced Inflammatory Response by Blocking iNOS Expression and NF-κB Activity in Macrophages

“…[1][2][3][4] Activated macrophages mediate the inflammatory response, releasing various pro-inflammatory molecules, free radical nitric oxide, and tumor necrosis factor-alpha (TNF-). 1,5) In mammals, 13 members of the toll-like receptor (TLR) family have been identified in the cell membranes of macrophages.…”

Sigma-1 Receptors Regulate Bcl-2 Expression by Reactive Oxygen Species-Dependent Transcriptional Regulation of Nuclear Factor κB

“…Of the most prominent actions of Sig-1Rs or those ligands is their robust cellular protective effect (Maurice and Lockhart, 1997;Bowen, 2000). Sig-1R agonists have been shown to promote cellular survival by preventing oxidative stress caused by ischemia (Schetz et al, 2007), diabetes (Smith et al, 2008), inflammation (Wang et al, 2008), and ␤-amyloid toxicity (Meunier et al, 2006).…”

Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

“…One of the major molecular sources of ROS is the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex (13,14). The involvement of NADPH oxidase has been studied in many models of ALI, and it has been recognized to contribute importantly (10,17,18,51). For example, in mice genetically deficient in the gp91 phox or p47 phox subunits of NADPH oxidase, septic lung injury and neutrophil infiltration were attenuated (17).…”