title: Inhibition of allergen-induced basophil activation by ASM-024, a nicotinic receptor ligand.
abstract: BACKGROUND
  Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet.
  
  
  OBJECTIVE
  We investigated surface receptor expression of nAChR α4, α7 and α1/α3/α5 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  nAChR α4, α7 and α1/α3/α5 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(-5) to 10(-)(3) M, 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).
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine, McMaster University, Hamilton, Ont., Canada.
authors: Brittany M
authors: BM
authors: Watson
authors: John Paul
authors: JP
authors: Oliveria
authors: Graeme M
authors: GM
authors: Nusca
authors: Steven G
authors: SG
authors: Smith
authors: Sue
authors: S
authors: Beaudin
authors: Benny
authors: B
authors: Dua
authors: Rick M
authors: RM
authors: Watson
authors: Evelynne Israël
authors: EI
authors: Assayag
authors: Yvon F
authors: YF
authors: Cormier
authors: Roma
authors: R
authors: Sehmi
authors: Gail M
authors: GM
authors: Gauvreau
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D001491:Basophils / Q000276:immunology*; D018592:Cross-Over Studies; D004246:Dimethylphenylpiperazinium Iodide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000097:blood; D011755:Pyrophosphatases / Q000097:blood; D011897:Random Allocation; D011978:Receptors, Nicotinic / Q000276:immunology*; D055815:Young Adult
chemical_list: C427944:ENPP3 protein, human; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases