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Br J Pharmacol. 2009 Jan;156(1):105-15. doi: 10.1111/j.1476-5381.2008.00012.x. Epub 2008 Dec 6.

Montelukast inhibits neutrophil pro-inflammatory activity by a cyclic AMP-dependent mechanism.

Author information

1
Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. ronald.anderson@up.ac.za

Abstract

BACKGROUND AND PURPOSE:

The objective of this study was to characterize the effects of the cysteinyl leukotriene receptor antagonist, montelukast (0.1-2 micromol x L(-1)), on Ca(2+)-dependent pro-inflammatory activities, cytosolic Ca(2+) fluxes and intracellular cAMP in isolated human neutrophils activated with the chemoattractants, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (1 micromol x L(-1)) and platelet-activating factor (200 nmol x L(-1)).

EXPERIMENTAL APPROACH:

Generation of reactive oxygen species was measured by lucigenin- and luminol-enhanced chemiluminescence, elastase release by a colourimetric assay, leukotriene B(4) and cAMP by competitive binding ELISA procedures, and Ca(2+) fluxes by fura-2/AM-based spectrofluorimetric and radiometric ((45)Ca(2+)) procedures.

KEY RESULTS:

Pre-incubation of neutrophils with montelukast resulted in dose-related inhibition of the generation of reactive oxygen species and leukotriene B(4) by chemoattractant-activated neutrophils, as well as release of elastase, all of which were maximal at 2 micromol x L(-1) (mean percentages of the control values of 30 +/- 1, 12 +/- 3 and 21 +/- 3 respectively; P < 0.05). From a mechanistic perspective, treatment of chemoattractant-activated neutrophils with montelukast resulted in significant reductions in both post-peak cytosolic Ca(2+) concentrations and store-operated Ca(2+) influx. These montelukast-mediated alterations in Ca(2+) handling by the cells were associated with a significant elevation in basal cAMP levels, which resulted from inhibition of cyclic nucleotide phosphodiesterases.

CONCLUSIONS AND IMPLICATIONS:

Montelukast, primarily a cysteinyl leukotriene (CysLT(1)) receptor antagonist, exhibited previously undocumented, secondary, neutrophil-directed anti-inflammatory properties, which appeared to be cAMP-dependent.

PMID:
19068077
PMCID:
PMC2697768
DOI:
10.1111/j.1476-5381.2008.00012.x
[Indexed for MEDLINE]
Free PMC Article

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