The Anti-allergic Cromones: Past, Present, and Future

Abstract

The anti-allergic cromones were originally synthesized in the 1960s by Fisons Plc, and the first drug to emerge from this program, disodium cromoglycate was subsequently marketed for the treatment of asthma and other allergic conditions. Whilst early studies demonstrated that the ability of the cromones to prevent allergic reactions was due to their 'mast cell stabilizing' properties, the exact pharmacological mechanism by which this occurred, remained a mystery. Here, we briefly review the history of these drugs, recount some aspects of their pharmacology, and discuss two new explanations for their unique actions. We further suggest how these findings could be used to predict further uses for the cromones.

Keywords: Annexin A1/FPR; GPR35; PKC; PP2A; cromones.

FIGURE 1

Nedocromil potentiates dexamethasone inhibition of TxB₂ release from U937 cells. The increased internalization of Anx-A1 (as assessed by western blotting) and concomitant inhibition of TxB₂ release (as assessed by ELISA assay) produced by escalating concentrations of nedocromil (0.2–10 nM) in the presence of a fixed concentration (2 nM) of dexamethasone. Figure reproduced with the permission from the rights holder, Elsevier (Yazid et al., 2009).

FIGURE 2

The inhibition by nedocromil and ketotifen of mediator release from Cord blood derived mast cells (CBDMCs) stimulated with compound 48/80 is dependent upon Anx-A1. CBDMCs were plated at a density of 2 × 10⁵ cells per well and the stipulated groups were treated with 20 μg/ml Anx-A1 neutralizing antibody or an irrelevant isotype control. Subsequently, the cells were pre-treated with either nedocromil (10 nM) or ketotifen (10 nM) for 5 min followed by compound 48/80 (10 μg/ml) stimulation for 10 min. To assess the effects of Anx-A1 removal, the cells were incubated with the Anx-A1 neutralizing antibody (or an irrelevant isotype control) only. Nedocromil and ketotifen produced consistent inhibition of histamine, but not control isotype matched non-neutralizing mAb. Data are expressed as mean ± SEM from n = 3 experiment and were analysed using one-way analysis of variance (ANOVA), followed by a Bonferroni post hoc test, ^∗p < 0.05, ^∗∗∗p < 0.001 vs unstimulated). Figure reproduced with the permission from the rights holder, Elsevier (Sinniah et al., 2016).

FIGURE 3

Schematic illustration of the role of Anx-A1 in mast cell degranulation and cromone action. (A) In the untreated, ‘resting’ mast cell, there is an intracellular pool of Anx-A1, a small proportion of which is externalized exerting a low-level tonic inhibitory influence on cell activation. (B) During stimulation by (e.g., Cpd 48/80) granule contents are released but Anx-A1 is also phosphorylated and released as a result of PKC activation. This provides some feedback control over the extent of degranulation. (C) In the presence of neutralizing anti-Anx-A1 mAbs, this feedback control is lost and degranulation is more extensive. (D) In mast cells pre-treated with nedocromil or cromoglycate, Anx-A1 is already externalized and fully engaged with inhibitory FPR receptors. This suppresses degranulation in response to degranulating stimuli (E) by inhibiting the activation response and ‘stabilizing’ the mast cell. (F) In the presence of the neutralizing mAb, however, this inhibitory influence is removed and extensive degranulation occurs.