title: Antiallergic and antiasthmatic effects of a novel enhydrazinone ester (CEE-1): inhibition of activation of both mast cells and eosinophils.
abstract: Activation of mast cells and eosinophils is a fundamental process in the pathophysiology of allergic diseases. We have previously reported that the novel enhydrazinone ester CEE-1 (ethyl 4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate) possesses potent anti-inflammatory activity. We have now tested whether the compound also possesses antiallergic and antiasthmatic effects in vitro and in vivo. The compound significantly inhibited degranulation and leukotriene C4 (LTC4) release from activated human eosinophils, as well as IgE-dependent degranulation and LTC4 release from passively sensitized rat basophilic leukemia cells and bone marrow-derived mouse mast cells. In human eosinophils, the drug was more potent in inhibiting degranulation than LTC4 release {IC50 = 0.4 μM [confidence interval (CI): 0.1-0.9] versus 3.8 μM (CI: 0.9-8.3)}, whereas in mast cells the reverse was essentially the case. The drug did not affect stimulus-induced calcium transients in eosinophils but significantly inhibited early phosphorylation of extracellular signal-regulated kinases 1/2 and p38-mitogen-activated protein kinases (MAPK). In vivo, topical application of 4.5-15 mg/kg of the compound significantly inhibited allergen-induced passive cutaneous anaphylaxis in mice. Similarly, in the mouse asthma model, the intranasal administration of 6.5-12.5 mg/kg of the compound significantly inhibited bronchial inflammation and eosinophil accumulation in bronchial lavage fluid, as well as abolishing airway hyper-responsiveness to methacholine. These results show that CEE-1 inhibits the activation of both mast cells and eosinophils in vitro, probably by blocking MAPK-activation pathways, and that these effects are translated into antiallergic and antiasthmatic effects in vivo. The compound, therefore, has potential application in the treatment of asthma and other allergic diseases.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine (C.I.E.), Department of Pharmacology and Therapeutics, Faculty of Pharmacy (A.Z.E.-H.), and Department of Anatomy, Faculty of Medicine (W.M.R.), Kuwait University, Kuwait City, Kuwait; and Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, Connecticut (I.O.E.) ezeamuzie@hsc.edu.kw.
authors.forename: Charles I
authors.initials: CI
authors.lastname: Ezeamuzie
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine (C.I.E.), Department of Pharmacology and Therapeutics, Faculty of Pharmacy (A.Z.E.-H.), and Department of Anatomy, Faculty of Medicine (W.M.R.), Kuwait University, Kuwait City, Kuwait; and Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, Connecticut (I.O.E.).
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: El-Hashim
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine (C.I.E.), Department of Pharmacology and Therapeutics, Faculty of Pharmacy (A.Z.E.-H.), and Department of Anatomy, Faculty of Medicine (W.M.R.), Kuwait University, Kuwait City, Kuwait; and Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, Connecticut (I.O.E.).
authors.forename: Waleed M
authors.initials: WM
authors.lastname: Renno
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine (C.I.E.), Department of Pharmacology and Therapeutics, Faculty of Pharmacy (A.Z.E.-H.), and Department of Anatomy, Faculty of Medicine (W.M.R.), Kuwait University, Kuwait City, Kuwait; and Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, Connecticut (I.O.E.).
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Edafiogho
mesh_terms: D000328:Adult; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D017997:Leukotriene C4 / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010659:Phenylhydrazines / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats
chemical_list: D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D003509:Cyclohexanecarboxylic Acids; D010659:Phenylhydrazines; C000590931:ethyl 4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate; D017997:Leukotriene C4; D007073:Immunoglobulin E; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium