Inotodiol, an antiasthmatic agent with efficacy and safety, preferentially impairs membrane-proximal signaling for mast cell activation

• Published in: International immunopharmacology 2023-04, Vol.117, p.109854, Article 109854
• Main Authors: Liu, Ye, Naskar, Rema, Acharya, Sabin, Ba Vinh, Le, Kim, Jin Hyeok, Lee, Jae-Young, Kim, Young Ho, Kang, Jong Seong, Hwang, Inkyu
• Format: Article
• Language: English
• Subjects: Animals; Anti-Asthmatic Agents - pharmacology; Anti-Asthmatic Agents - therapeutic use; Asthma; Asthma - drug therapy; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Disease Models, Animal; FcεRI signaling; Inotodiol; Mast cell; Mast Cells; Mice; Oral formulation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.109854

•Inotodiol in a lipid-based formulation shows desirable oral bioavailability.•Inotodiol’s therapeutic index for asthma is >8 times better than dexamethasone’s.•Inotodiol selectively inhibits mast cell function both in vitro and in vivo.•Inotodiol suppresses receptor-proximal signaling for mast cell activation. While inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, due to compliance, drug safety, and resistance issues, new medications to replace ICSs are in high demand. Inotodiol, a fungal triterpenoid, showed a unique immunosuppressive property with a preference for mast cells. It exerted a mast cell-stabilizing activity equally potent to dexamethasone in mouse anaphylaxis models when orally administered in a lipid-based formulation, upgrading bioavailability. However, it was four to over ten times less effective in suppressing other immune cell subsets, depending on the subsets, than dexamethasone showing invariably potent inhibition. Accordingly, inotodiol affected the membrane-proximal signaling for activating mast cell functions more profoundly than other subsets. Inotodiol also effectively prevented asthma exacerbation. Importantly, considering the no-observed-adverse-effect level of inotodiol was over 15 times higher than dexamethasone, its therapeutic index would be at least eight times better,implying that inotodiol is a viable option for replacing CSs in treating asthma.