title: Azelastine desensitization of transient receptor potential vanilloid 1: a potential mechanism explaining its therapeutic effect in nonallergic rhinitis.
abstract: BACKGROUND
  Capsaicin, a prototypic transient receptor potential vanilloid 1 (TRPV1) agonist, has been shown to be more clinically effective in the treatment of nonallergic rhinitis (NAR) compared with other rhinitis subtypes. Azelastine has also been found to be clinically effective in the treatment of NAR but its mechanism(s) of action is still poorly elucidated. This study was designed to determine, using in vitro cell lines, whether topical therapies including azelastine have activity on TRPV1 ion channels similar to capsaicin.
  
  
  METHODS
  The effects of capsaicin (1 μM), azelastine (30 μM), bepotastine (10 μM), olopatadine (10 μM), and fluticasone (200 μM) on TRPV1 channels using mice neuronal cells (Cath.a), as surrogates for submucosal sensory neurons, and human nasal epithelial cells (hNEC) were determined and compared. For azelastine, bepotastine, and capsaicin, which elicited an agonist effect on TRPV1, live cell [Ca(2+)] signaling in Cath.a cells and hNECs expressing TRPV1 were performed in the absence and presence of capsazepine at 10 μM (a TRPV1 antagonist) or using wild-type mouse embryonic fibroblasts (wtMEFs) that express TRPV1 ion channels and TRPV1 homozygous null mutant (TRPV1-/-) knockout MEF cells as controls to establish TRPV1 channel selectivity. As azelastine has previously been found clinically effective in NAR, additional experiments were performed to determine its ability to desensitize TRPV1 ion channels and its effect on regulating intracellular calcium homeostasis.
  
  
  RESULTS
  Cath.a cells treated with azelastine, bepotastine, or capsaicin showed a significant increase in TRPV1-dependant (Ca(2+)) specific cytosolic fluorescence. Continuous treatment with azelastine or capsaicin resulted in desensitization of TRPV1 channels. In hNECs, azelastine stimulation resulted in Ca(2+) shifts from the cytosol to mitochondria and overexpression of hematopoietic cell-specific Lyn substrate 1-associated protein X1, which may thus be effective in cytosolic Ca(2+) homeostasis.
  
  
  CONCLUSIONS
  Azelastine, similar to capsaicin, exhibits direct activity on TRPV1 ion channels that may represent a novel mechanistic pathway explaining its clinical efficacy in NAR.
authors: Division of Allergy Section, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Umesh
authors: U
authors: Singh
authors: Jonathan A
authors: JA
authors: Bernstein
authors: Lauren
authors: L
authors: Haar
authors: Kristin
authors: K
authors: Luther
authors: Walter K
authors: WK
authors: Jones
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003990:Dibenzoxepins / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D000068298:Fluticasone; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D000069605:Olopatadine Hydrochloride; D010793:Phthalazines / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012220:Rhinitis / Q000188:drug therapy*; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000730:Androstadienes; D003990:Dibenzoxepins; D010793:Phthalazines; D010880:Piperidines; D011725:Pyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000069605:Olopatadine Hydrochloride; D000068298:Fluticasone; C108476:bepotastine; C071423:capsazepine; D002211:Capsaicin; C020976:azelastine