Therapeutic effects of R8, a semi-synthetic analogue of Vasicine, on murine model of allergic airway inflammation via STAT6 inhibition.

Abstract

This is a follow-up study of our previous work in which we screened a series of Vasicine analogues for their anti-inflammatory activity in a preventive OVA induced murine model of asthma. The study demonstrated that R8, one of the analogues, significantly suppressed the Th2 cytokine production and eosinophil recruitment to the airways. In the present study, we have been using two standard experimental murine models of asthma, where the mice were treated with R8 either during (preventive use) or after (therapeutic use) the development of asthma features. In the preventive model, R8 reduced inflammatory cell infiltration to the airways, OVA specific IgE and Th2 cytokine production. Also, the R8 treatment in the therapeutic model decreased methacholine induced AHR, Th2 cytokine release, serum IgE levels, infiltration of inflammatory cells into the airways, phosphorylation of STAT6 and expression of GATA3. Moreover, R8 not only reduced goblet cell metaplasia in asthmatic mice but also reduced IL-4 induced Muc5AC gene expression in human alveolar basal epithelial cells. Further, R8 attenuated IL-4 induced differentiation of murine splenocytes into Th2 cells in vitro. So, we may deduce that R8 treatment profoundly reduced asthma features by attenuating the differentiation of T cells into Th2 cells by interfering with the binding of IL-4 to its receptor in turn decreasing the phosphorylation of STAT6 and expression of GATA3 in murine model of asthma. These preclinical findings suggest a possible therapeutic role of R8 in allergic asthma.

• Authors: Sheikh Rayees, Ulaganathan Mabalirajan, Wajid Waheed Bhat, Shafaq Rasool, Rafiq Ahmad Rather, Lipsa Panda, Naresh Kumar Satti, Surrinder Kumar Lattoo, Balaram Ghosh, Gurdarshan Singh
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 26 Issue 1 Pg. 246-56 (May 2015) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 25863236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• 5-benzoyl-5a,6,7,8,9,10-hexahydroazepino(2,1-b)quinazoline-12(5H)-one
• Alkaloids
• Anti-Asthmatic Agents
• Azepines
• Cytokines
• Quinazolines
• Quinazolinones
• STAT6 Transcription Factor
• Stat6 protein, mouse
• Immunoglobulin E
• vasicine
• Ovalbumin

Topics

• Alkaloids (chemistry)
• Animals
• Anti-Asthmatic Agents (administration & dosage, chemistry, therapeutic use, toxicity)
• Asthma (drug therapy, immunology, metabolism)
• Azepines (administration & dosage, chemistry, therapeutic use, toxicity)
• Cytokines (analysis, genetics)
• Disease Models, Animal
• Gene Expression (drug effects)
• Immunoglobulin E (blood)
• Lung (drug effects, metabolism, pathology)
• Male
• Mice, Inbred BALB C
• Ovalbumin (immunology)
• Quinazolines (chemistry)
• Quinazolinones (administration & dosage, chemistry, therapeutic use, toxicity)
• STAT6 Transcription Factor (antagonists & inhibitors)
• Toxicity Tests