Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS.

Abstract

BACKGROUND AND PURPOSE:

In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages.

EXPERIMENTAL APPROACH:

Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay.

KEY RESULTS:

AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%.

CONCLUSION AND IMPLICATIONS:

Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression.

• Authors: E Finkin-Groner, D Moradov, H Shifrin, C Bejar, A Nudelman, M Weinstock
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 4 Pg. 1101-13 (Feb 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25322956 (Publication Type: Journal Article)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Carbamates
• Cytokines
• Indoles
• Lipopolysaccharides
• Receptors, Nicotinic
• Cholinesterases

Topics

• Acute Lung Injury (drug therapy, immunology)
• Animals
• Carbamates (pharmacology, therapeutic use)
• Cell Line
• Cells, Cultured
• Cholinesterases (metabolism)
• Cytokines (immunology)
• Female
• Indoles (pharmacology, therapeutic use)
• Lipopolysaccharides
• Macrophages, Peritoneal (drug effects, immunology)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Receptors, Nicotinic