A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C-δ-dependent signaling pathway.

Abstract

Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti-allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869-6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13-acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4-diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA-induced phosphorylation of PKCδ at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCδ activation.

• Authors: Manik Chandra Shill, Hiroyuki Mizuguchi, Sanmoy Karmakar, Takuya Kadota, Pulok K Mukherjee, Yoshiaki Kitamura, Yoshiki Kashiwada, Hisao Nemoto, Noriaki Takeda, Hiroyuki Fukui
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 30 Pg. 18-26 (Jan 2016) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 26619301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• 4-methoxybenzofuran-5-carboxamide
• Anti-Allergic Agents
• Benzofurans
• Cytokines
• Receptors, Histamine H1
• Toluene 2,4-Diisocyanate
• Histamine
• Protein Kinase C-delta

Topics

• Animals
• Anti-Allergic Agents (administration & dosage)
• Benzofurans (administration & dosage)
• Cytokines (metabolism)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• HeLa Cells
• Histamine (metabolism)
• Humans
• Male
• Protein Kinase C-delta (metabolism)
• Rats
• Rats, Inbred Strains
• Receptors, Histamine H1 (genetics, metabolism)
• Rhinitis, Allergic (chemically induced, drug therapy)
• Tephrosia (immunology)
• Th2 Cells (drug effects, immunology)
• Toluene 2,4-Diisocyanate (immunology)