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Published on: May 2, 2018
Anti-inflammatory effects of dimemorfan on inflammatory cells and LPS-induced endotoxin shock in mice
1Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.
Background And Purpose:
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.
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 LPS-induced 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 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 And Implications:
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.
Insights
Dimemorfan reduces inflammatory responses in neutrophils and microglial cells by inhibiting reactive oxygen species and pro-inflammatory cytokine production. This sigma1 receptor-independent action offers protective effects against endotoxin shock.
Area of Science:
- Pharmacology
- Immunology
- Neuroscience
Background:
- Dimemorfan, a sigma1 receptor agonist, demonstrates neuroprotection in animal models.
- Its impact on inflammatory cells and systemic inflammation requires further investigation.
Purpose of the Study:
- To elucidate the effects of dimemorfan on inflammatory cells and systemic inflammation.
- To investigate the mechanisms underlying dimemorfan's anti-inflammatory actions.
Main Methods:
- Assessed dimemorfan's effects on neutrophils and microglial cells stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS).
- Evaluated dimemorfan's efficacy in an LPS-induced endotoxin shock mouse model.
- Investigated mechanisms including reactive oxygen species (ROS) production, CD11b expression, nitric oxide (NO) production, cytokine levels, NADPH oxidase (NOX) activity, and nuclear factor kappa-B (NF-kappaB) signaling.
Main Results:
- Dimemorfan decreased ROS and CD11b expression in neutrophils, independent of sigma1 receptors.
- In microglial cells, dimemorfan inhibited LPS-induced ROS, NO, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha (TNF-alpha) by inhibiting NOX activity and NF-kappaB signaling.
- In vivo, dimemorfan reduced plasma TNF-alpha, and neutrophil infiltration and oxidative stress in the lungs and liver.
Conclusions:
- Dimemorfan exhibits anti-inflammatory effects through sigma1 receptor-independent modulation of intracellular calcium, NOX activity, and NF-kappaB signaling.
- These mechanisms lead to the inhibition of inducible nitric oxide synthase (iNOS) expression and pro-inflammatory cytokine production.
- Dimemorfan's actions contribute to its protective effects against endotoxin shock in mice.
