In-vitro and in-vivo anti-allergic effects of magnolol on allergic rhinitis via inhibition of ORAI1 and ANO1 channels

• Published in: Journal of ethnopharmacology Vol. 289; p. 115061
• Main Authors: Phan, Hong Thi Lam, Nam, Yu Ran, Kim, Hyun Jong, Woo, Joo Han, NamKung, Wan, Nam, Joo Hyun, Kim, Woo Kyung
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.05.2022
• Subjects: Allergic rhinitis; Animals; Anoctamin 1; Anoctamin-1 - antagonists & inhibitors; Anti-Allergic Agents - administration & dosage; Anti-Allergic Agents - isolation & purification; Anti-Allergic Agents - pharmacology; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - isolation & purification; Biphenyl Compounds - pharmacology; Calcium release-activated calcium channel protein 1; Calcium-activated chloride channel; Cell Line, Tumor; Cytokines - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Flowers; HEK293 Cells; Humans; Lignans - administration & dosage; Lignans - isolation & purification; Lignans - pharmacology; Magnolia - chemistry; magnolol; Mice; Mice, Inbred BALB C; Neoplasm Proteins - antagonists & inhibitors; ORAI1 Protein - antagonists & inhibitors; Ovalbumin; Patch-Clamp Techniques; Rhinitis, Allergic - drug therapy; CaCC; IL; [Ca2+]i; IgE; FM; NLF; CFSE; Calcium release-activated calcium channel protein 1; IP3; ANO1; AR; TG; magnolol; Allergic rhinitis; ISC; SOCE; ORAI1; OVA; DPBS; Calcium-activated chloride channel; CFTR; Anoctamin 1; Th2
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2022.115061

Flos Magnoliae (the dried flower buds of Magnolia biondii Pamp, FM) is a known herbal traditional medicine used for the symptomatic relief of nasal congestion and rhinorrhea caused by rhinitis and sinusitis. Magnolol, a neolignan from the magnolia family, is a secondary metabolite known to have anti-allergic and anti-inflammatory effects. However, the underlying mechanisms and therapeutic effect of magnolol in the treatment of allergic rhinitis (AR) remain elusive. Anoctamin 1 (ANO1), a calcium-activated anion channel, mediates mucus and electrolyte secretion in nasal airway epithelial cells, whereas calcium release-activated calcium channel protein 1 (ORAI1) participates in the activation of T-lymphocytes and mast cells. The aim of our study is to understand the mechanisms of action of magnolol against AR, i.e., whether it acts through the modulation of ANO1 and ORAI1 channels that are expressed in nasal epithelial cells and T-lymphocytes, respectively. Whole-cell patch clamp was used to record the activity of ORAI1 and ANO1 ion channels in ORAI1 or ANO1 overexpressed HEK293T cells, while the Ussing chamber apparatus was used to measure electrolyte transport via the epithelium, in Calu-3 cells cultured in an air-liquid interface. Additionally, calcium imaging of Jurkat T-lymphocytes was used to assess changes in the intracellular calcium concentration. Magnolol toxicity was assessed using the CCK-8 assay, and its effect on T-lymphocyte proliferation was measured by labeling human primary T-lymphocytes with carboxyfluorescein succinimidyl ester. Finally, OVA-induced Balb/c mice were employed to evaluate the effect of magnolol on nasal symptoms, as well as cytokine and eosinophil infiltration in AR. Magnolol inhibits ORAI1 and ANO1 channels in a concentration-dependent manner. Magnolol (30 μM) inhibits anti-CD3 induced cellular proliferation and production of IL-2 via ORAI1 channels in T-lymphocytes. Further, ATP-induced electrolyte transport mediated by ANO1 channels is significantly inhibited by magnolol in IL-4 sensitized Calu-3 cells. Notably, 300 μM magnolol significantly attenuates cytokine and eosinophil infiltration, thus alleviating AR symptoms in mice OVA-induced AR. Magnolol may be a promising therapeutic agent for the treatment and prevention of AR. [Display omitted] •Magnolol inhibited ORAI1 and ANO1 channels.•Magnolol suppressed CD4+ T-cell proliferation, IL-2 production, and [Ca2+]i.•Magnolol inhibited CaCC and short-circuit currents, but not CFTR in Calu-3 cells.•Magnolol attenuated nasal symptoms, and cytokine/eosinophil infiltration in AR mice.•Magnolol may be a potential therapeutic agent in the treatment and prevention of AR.