Anti-inflammatory effects of dimemorfan on inflammatory cells and LPS-induced endotoxin shock in mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wang
Y-H
YH
Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.
Shen
Y-C
YC
Liao
J-F
JF
Lee
C-H
CH
Li
C-H
CH
Chou
C-Y
CY
Liou
K-T
KT
Chou
Y-C
YC
D000818:Animals; D000893:Anti-Inflammatory Agents; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005455:Fluorescent Antibody Technique; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D051379:Mice; D009019:Morphinans / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000473:pathology* / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D009019:Morphinans; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D009569:Nitric Oxide; D009240:N-Formylmethionine Leucyl-Phenylalanine; C012621:dimemorfan; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium