Drug repositioning of anti-microbial agent nifuratel to treat mast cell-mediated allergic responses

Abstract

Objectives: Our objective was to assess the effects and mechanisms of nifuratel on IgE-mediated mast cell (MC) degranulation and anaphylaxis in both in vitro and in vivo settings. Methods: The anti-allergic activity of nifuratel was evaluated in mast cell cultures and the passive cutaneous anaphylaxis (PCA) model. The effects of nifuratel on signaling pathways stimulated by antigen in mast cells were measured by immunoblotting, immunoprecipitation, in vitro protein tyrosine kinase assay, and other molecular biological methods. Results: Nifuratel reversibly inhibited antigen-induced degranulation of MCs (IC50, approximately 0.34 μM for RBL-2H3 cells; approximately 0.94 μM for BMMCs) and suppressed the secretion of inflammatory cytokines IL-4 (IC50, approximately 0.74 μM) and TNF-α (IC50, approximately 0.48 μM). Mechanism studies showed that nifuratel inhibited the phosphorylation of Syk by antigen via the inhibition of recruitment of cytosolic Syk to the ɣ subunit of FcεRI, and decreased the activation of Syk downstream signaling proteins LAT, Akt, and MAPKs. Finally, nifuratel dose-dependently suppressed the IgE-mediated passive cutaneous anaphylaxis in mice (ED50, approximately 22 mg/kg). Conclusion: Our findings suggest that nifuratel inhibits pathways essential for the activation of mast cells to suppress anaphylaxis, thereby indicating that the anti-microbial drug, nifuratel, could be a potential drug candidate for IgE-mediated allergic disorders.