Mechanism of action of the nonlipophilic antiallergic drug eclazolast (REV 2871) in the inhibition of mediator release in a mast cell model

Objective and Design. In this study, we compared eclazolast with other lipophilic antiallergic drugs, relating to effects on signal transduction pathways, leading to inhibition of exocytosis in a rat basophilic leukemia cell (RBL-2H3). Materials and Methods: Effects of the drugs on mediator release (beta-hexosaminidase, arachidonic acid metabolites) after Fc epsilon RI activation in RBL-2H3 cell were quantified. Furthermore, effects of the drugs on cellular signalling (Ca2+ influx, intracellular Ca2+ concentration, inositol 1,4,5-trisphosphate (IP3) concentration) were assayed. Effects of the drugs on bilayer and cell membranes have been recorded. Results: It is shown that eclazolast down-regulates IP3 levels. In contrast to lipophilic drugs, eclazolast does not affect artificial bilayers and erythrocyte membranes, and there is no effect on thapsigargin induced Ca2+ influx. The effect of eclazolast was highly dependent on the antigen concentration with which the cells were triggered. Conclusions: The mechanism of action of eclazolast is deviant from lipophilic antiallergic agents. It inhibits exocytosis by intracellularly affecting only direct Fc epsilon RI linked processes and not through inhibition of Ca2+ influx channels, as found for membrane disturbing lipophilic drugs.