Epimedium brevicornum Maxim and Ligustrum lucidum Ait enhance glucocorticoid-associated anti-inflammatory effects in asthma via the cAMP/PKA/CREB signaling pathway

Ethnopharmacological relevance: Traditional Chinese medicine (TCM) attributes chronic asthma to "kidney deficiency", a condition traditionally associated with poor responsiveness to glucocorticoid therapy. The herbal pair Epimedium brevicornum Maxim and Ligustrum lucidum Ait (EL) is commonly prescribed to tonify the kidney and alleviate asthma-related symptoms. Emerging evidence suggests that EL and its active constituents, icariin and oleanolic acid (IO), can enhance glucocorticoid-associated anti-inflammatory effects; however, the underlying molecular mechanism remains incompletely understood.

Aim: This study aimed to investigate whether EL and IO modulate glucocorticoid-associated responses in asthma through the cAMP/PKA/CREB signaling pathway and to evaluate the role of CREB as a key downstream mediator.

Methods: An ovalbumin (OVA)-induced asthma model in rats and interleukin-4 (IL-4)-stimulated human bronchial epithelial cells (HBECs) were established. In vivo, asthmatic rats received dexamethasone (Dex), EL decoction, or their combination. The EL decoction was prepared form authenticated botanical crude drugs following pharmacopoeial procedures. In vitro, HBECs were treated with Dex, IO, or their combination, with or without the CREB inhibitor KG501. Inflammatory responses, oxidative stress, and cAMP/PKA/CREB signaling-related markers were assessed using histology, ELISA, qRT-PCR, and Western blotting. Additional in vivo experiments were performed to evaluate the impact of CREB inhibition on EL-mediated Effects.

Results: OVA-challenged rats exhibited elevated IgE and IL-6 levels, increased oxidative stress (↑MDA, ↓SOD), and marked suppression of the cAMP/PKA/CREB signaling axis, as evidenced by reduced phosphorylation of PKA and CREB and decreased p-PKA/PKA and p-CREB/CREB ratios. Treatment with EL decoction, particularly when combined with Dex, was associated with attenuation of airway inflammation, partial restoration of redox balance, and reactivation of cAMP/PKA/CREB-related signaling. Pharmacological inhibition of CREB using KG501 partially abrogated these protective effects both in vivo and in vitro, supporting a critical role for CREB in mediating EL- and IO- associated responses.

Asthma; Epimedium brevicornum Maxim; Glucocorticoid sensitivity; Icarrin; KG501; Ligustrum lucidum Ait; Oleanlic acid; cAMP/PKA/CREB.