Mechanism of Action of an Antiallergic Agent, Amlexanox (AA-673), in Inhibiting Histamine Release from Mast Cells

Abstract

Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10^––8––10^––6M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10^––8, 10^––7 and 10^––6M of amlexanox combined with 10^––7M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10^––6––10^––4M increased the cAMP content 1.7––3.8-fold, and a combination of 10^––4M IBMX and 10^––7M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20–30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE₂, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC₅₀ value was 1.4 × 10^––⁵M, and its inhibitory activity was half that of IBMX. These results suggest that amlexanox inhibits histamine release by augmenting the cAMP content in mast cells, and that this augmentation is caused by enhancing the cAMP generation and, additively, by inhibiting cAMP phosphodiesterase.

Inhibition of Immediate Allergic Reactions by Ethanol Extract from Plumbago zeylanica Stems

“…The findings suggested that EPZ inhibited IgE-dependent or -independent degranulation and exocytosis of mast cells, consequent mediator release and anaphylactic responses. Weston et al 18,19) have reported that agents that induce and sustain elevation in intracellular cAMP attenuate the stimulated release of mediators from mast cells and basophils. EPZ 50 mg/ml, incubated with rat mast cells, dramatically increased the intracellular cAMP content.…”

Electron Microscopic Studies on the Inhibition of Degranulation of Rat Mast Cells by a Novel Anti-Allergic Agent, PTPC

“…The increase in cyclic AMP content caused by PTPC correlated with its inhibitory effect on the IgE mediated histamine release. Makino et al (23) have reported that amlexanox, an anti-allergic agent, inhibited the histamine release by increasing the cyclic AMP con tent in mast cells. They also proposed that increase of cyclic AMP was caused by enhancing the cyclic AMP synthesis in addition to inhibiting cyclic AMP phospho diesterase.…”

Inhibitory effects of epigallocatechin gallate on compound 48/80-inducedmast cell activation and passive cutaneous anaphylaxis

“…The close correlations among the concentration of the histamine-releasing stimulus, calcium ion influx (Raison et al, 1999), and the amount of released histamine suggest a cause-and effect-relationship between the influx of calcium and release of histamine (Hachisuka et al, 1988;Daniele, 1989;Lorenz et al, 1998). And the release of histamine is depressed by an increase in the intracellular cAMP (Makino et al, 1987;Alfonso et al, 2000;Sarkar et al, 2003). So, we examined the effect of EGCG on second messenger such as calcium and cAMP.…”

“…But EGCG inhibited the compound 48/80-induced cAMP reduction of RPMCs. The release of histamine is depressed by an increase in the intracellular cAMP content due to the activation of adenylate cyclase or inhibitor of cAMP phosphodiesterase (Makino et al, 1987;Alfonso et al, 2000;Sarkar et al, 2003). The inhibitory effect of EGCG on mast cell degranulation and histamine release from mast cells may be related to the prevention of an increase of intracellular calcium content owing to elevation of the intracellular cAMP level by increase of adenylate cyclase activity or inhibition of the cAMP phosphodiesterase.…”