Cromoglycate: Breathing life into an old asthma drug

Abstract

DiSodium Cromoglycate (DSCG) has been used as an effective asthma therapy for over 50 years with a good clinical safety history but with poor pharmacokinetics. An analogue of DSCG with a more preferable profile could aid the development of novel asthma drugs, however, the mechanism of action is currently unknown. Previous pre-clinical data has linked the late asthmatic response (LAR) with activation of the Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel on airway sensory nerves 1 and DSCG has been shown to inhibit this response in clinical studies 2 . Thus we hypothesised that the effectiveness of DSCG is via the modulation of sensory nerves. In a rat allergic model of asthma, DSCG inhibited the LAR. Using rat, guinea pig and human isolated vagal nerves and rat airway vagal ganglia cells it was shown that DSCG modulates TRPA1-driven nerve activation and calcium influx. DSCG is an agonist at the orphan G protein coupled receptor 35 (GPR35). TRPA1 and GPR35 are expressed in vagal ganglia cells therefore it was hypothesised that GPR35 is involved in the mechanism by which DSCG inhibits TRPA1 mediated sensory nerve activity. Utilising a range of GPR35 agonists and channel blockers we identified that this effect of DSCG was dependent on GPR35 via signalling through Gi and N-type calcium channels. Finally, using in vivo models we show that DSCG inhibition of airway nerve firing and LAR was attenuated by the GPR35 antagonist, ML 145. DSCG attenuates the TRPA1-mediated nerve-driven asthma symptoms via a direct action on sensory nerves through GPR35. Thus, GPR35 could be a novel, safe and effective target for the development of future asthma therapy. Raemdonck et al (2012) Thorax 67: 19 Howell & Altounyan (1967) Lancet 2: 539.