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 anti-allergic and anti-asthmatic 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 LTC4release from passively-sensitized rat basophilic leukemia cells (RBL-2H3) and bone marrow-derived mouse mast cells (BMMC). 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] vs. 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 ERK1/2 and p38 MAP kinases. In vivo, topical application of 4.5-15 mg/kg of the compound significantly inhibited allergen-induced passive cutaneous anaphylaxis (PCA) in mice. Similarly, in the mouse asthma model, the intra-nasal 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, abolished 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 MAP kinases activation pathways, and that these effects are translated into anti-allergic and anti-asthmatic effects in vivo. The compound, therefore, has a potential application in the treatment of asthma and other allergic diseases.
KEYWORDS:
allergy; asthma; cycteinyl leukotrienes; drug discovery; immunopharmacology; lung inflammation; mast cells; pulmonary pharmacology; respiratory pharmacology
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