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 C 4 (LTC 4 ) release from activated human eosinophils, as well as IgE-dependent degranulation and LTC 4 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 LTC 4 release {IC 50 5 0.4 mM [confidence interval (CI): 0.1-0.9] versus 3.8 mM (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 hyperresponsiveness 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.

Onion Bulb Extract Downregulates EGFR/ERK1/2/AKT Signaling Pathway and Synergizes With Steroids to Inhibit Allergic Inflammation

“…Our data also show that HDM challenge resulted in the induction of AHR, a characteristic feature of both clinical and preclinical asthma that is not easily amenable to asthma therapy ( Busse, 2010 ; Ezeamuzie et al, 2014 ). Our findings show that treatment with OBE had no effect on this parameter.…”

“…Airway responsiveness was measured 24 h after last HDM or PBS challenge, using a separate set of animals using the Buxco FinePointe series RC site (DSI, Wilmington, NC) as described previously ( Queto et al, 2010 ; Ezeamuzie et al, 2014 ; Correa et al, 2017 ). Briefly, mice were anesthetized with an intraperitoneal injection of ketamine/xylazine (1:0.1 mg/kg) cocktail and tracheotomized with a steel 18-gauge cannula.…”

“…The methods and protocol for these experiments were performed in accordance with and approved by the “Ethical Committee of the Faculty of Medicine, Kuwait University”. Granulocytes were isolated from heparinized (10 IU/ml) blood by erythrocyte sedimentation, followed by percoll gradient centrifugation as reported recently ( Ezeamuzie et al, 2014 ). Eosinophils were separated using negative selection with the immunomagnetic method as previously described ( Hansel et al, 1991 ).…”

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

“…Asthma is a major cause of chronic morbidity and mortality throughout the world and its prevalence increased considerably over the past 20 years, especially in children (Stevenson and Birrell, 2011;Nagai, 2012;Ezeamuzie et al, 2014). Asthma is a condition characterized by persistent or recurrent airway inflammation, airway hyperresponsiveness (AHR), chronic airway remodeling and various degrees of reversible airflow limitation (Bousquet et al, 2000;Nials and Uddin, 2008;Blume and Davies, 2013).…”

The IL-15 / sIL-15Rα complex modulates immunity without effect on asthma features in mouse

“…The mice were placed in the Finepoint RC system room (Data Sciences International, St Paul, Minnesota) and connected to a ventilator. Mechanical ventilation was started with a respiratory rate of 150/min and a tidal volume of 0.15 mL as previously described [16]. The mice were nebulized with NaCL (baseline reference data) then with methacholine at increasing doses (5, 10, 15 and 20 mg/ L).…”