Effects of the combination of Epimedium brevicornum Maxim, Ligustrum lucidum Ait and Dexamethasone on asthmatic rats by endogenous glucocorticoid pathway.

Ethnopharmacological Relevance: The theory of traditional Chinese medicine (TCM) believes that kidney deficiency is the fundamental cause of chronic refractory asthma, accompanied by pathological changes such as airway remodeling and a reduction of endogenous glucocorticoid (GC) synthesis. The combination of Epimedium brevicornum Maxim (EB) and Ligustrum lucidum Ait (LL) is frequently used in TCM for kidney tonifying and the alleviation of asthma symptoms. This approach is based on Pei-Ben formula, a renowned treatment for asthma developed by the distinguished Shanghai Practitioner, Professor Huiguang Xu, over 30 years of clinical experience. Long-term use of exogenous GC in the treatment of asthma lead to the inhibition of endogenous GC synthesis and further hypothalamic-pituitary-adrenal (HPA) axis function. Our previous experiments confirmed that the combination of Epimedium brevicornum Maxim and Ligustrum lucidum Ait (EL) with dexamethasone (Dex) enhances kidney Yin and Yang, boosts endogenous GC levels, and improves airway remodeling and HPA axis function in asthmatic rats. However, the underlying mechanism remains unclear.

Aims: This study aimed to investigate the regulatory effect of EL with Dex on endogenous GC pathway in asthmatic rats.

Methods: We employed an ovalbumin (OVA)-induced asthma rat model and an OVA-induced asthma rat model with Metyrapone (Met, an inhibitor of endogenous GC synthesis) intervention to evaluate the effects of Dex, EL and their combination (EL + Dex) on asthma treatment. The assessment included the lung histopathology, GC receptors (GR) countent and GC-GR binding in bronchoalveolar lavage fluid (BALF), corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT), cortisol (COR), interleukin 6 (IL-6), and immunoglobulin E (IgE) in serum, GC metabolites in urine, and hydroxysteroid dehydrogenase (HSD) 11B1, HSD11B2, cytochrome P450 family 11 subfamily B member 1 (CYP11B1) and steroidogenic factor 1 (SF1) in lung, liver, and adrenal gland.

Results: In the OVA-induced asthma model, we found that endogenous GC synthesis was suppressed in both the asthma group and the Dex group. The combination of EL and Dex could enhance HPA axis function, increase protein expression of key endogenous GC synthesis factors (HSD11B1, HSD11B2 in lung; CYP11B1, SF1 in adrenal; HSD11B2, CYP11B1 in liver), and improve the level of endogenous GC synthesis. In the OVA-induced asthma model with Met intervention, we observed a highly significant endogenous suppression in both the asthma + Met group and the Dex group. Additionally, the use of EL, either alone or in combination with Dex, demonstrated a significant effect in improving HPA axis function and enhancing the protein expression of key endogenous GC synthesis factors (HSD11B1, HSD11B2 in lung; HSD11B1, HSD11B2, CYP11B1, SF1 in adrenal; HSD11B1 in liver). In both asthma models, the combination of EL and Dex could relieve the pathological changes of airway inflammation and airway remodeling, and enhance GC-GR binding capacity.

Conclusions: This study reveals that the combined use of EL and Dex could improve airway inflammation and airway remodeling in asthma through enhancing HPA axis function, endogenous GC synthesis, and GC-GR binding, offering a promising therapeutic strategy for asthma management.