Inhibition of Allergen-Induced Basophil Activation by ASM-024, a Nicotinic Receptor Ligand
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<b><i>Background:</i></b> Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. <b><i>Objective:</i></b> We investigated surface receptor expression of nAChR α<sub>4</sub>, α<sub>7</sub> and α<sub>1</sub>/α<sub>3</sub>/α<sub>5</sub> subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. <b><i>Methods:</i></b> Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. <b><i>Results:</i></b> nAChR α<sub>4</sub>, α<sub>7</sub> and α<sub>1</sub>/α<sub>3</sub>/α<sub>5</sub> receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10<sup>-5</sup> to 10<sup>-</sup><sup>3</sup> <smlcap>M</smlcap>, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). <b><i>Conclusion:</i></b> This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses.
