A multi-target combinatorial therapy of MDBA alleviates atopic dermatitis via synchronized immunosuppression and barrier repair.

Abstract

The pathogenesis of atopic dermatitis (AD) involves immune dysregulation and skin barrier dysfunction. Existing therapies often struggle to concurrently address immune modulation and barrier repair, and long-term use may lead to side effects. This study systematically evaluated the comprehensive potential and mechanisms of action of MDBA, a complex comprising matrine (M), dipotassium glycyrrhizinate (D), alpha-bisabolol (B), and asiaticoside (A), which has been employed for the first time to treat AD. In a calcipotriol (MC903)-induced mouse and guinea pig models of AD-like dermatitis, topical application of MDBA significantly ameliorated disease severity, as evidenced by reduced EASI scores and epidermal thickness. Mechanistic investigations revealed that the therapeutic effects of MDBA are likely mediated through the inhibition of the phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, achieving dual regulation: on one hand, it effectively suppressed the overactivation of Th2-type immunity, demonstrated by decreased levels of interleukin (IL)-4, IL-13, and IL-31 in ear tissue and serum, reduced infiltration of cluster of differentiation 4-positive T (CD4T) cells, and lower serum total immunoglobulin E (IgE) levels and mast cell infiltration; on the other hand, it potently promoted skin barrier repair, upregulating the expression of various key barrier proteins including filaggrin (FLG), involucrin, and claudin-1. Furthermore, in an independent physical barrier disruption model induced by tape stripping, MDBA also demonstrated excellent restorative function, accelerating epidermal recovery, reducing transepidermal water loss, and normalizing ceramide levels. Safety assessment revealed no significant organ toxicity or functional abnormalities. Thus, MDBA is a promising AD therapy that targets the PI3K/AKT pathway to deliver concurrent immunosuppressive and barrier-repairing effects.