Investigation of the therapeutic efficacy of dimethyl fumarate in an OVA-LPS induced asthma model in mice

Allergic asthma, the most common subtype of asthma, significantly impairs patients' quality of life, and a definitive cure is yet to be established. Its pathogenesis involves multiple factors, including oxidative stress, inflammation, and alterations in cellular metabolism. In this study, we aimed to investigate the therapeutic effects of dimethyl fumarate (DMF), in an ovalbumin (OVA) and lipopolysaccharide (LPS)-induced asthma model. The study focused on tracheal contractility, protein expression changes in lung tissue, parenchymal and peribronchial inflammation, and alterations in cellular metabolites. Female Balb/c mice were sensitized and challenged over a 21-day experimental protocol using intraperitoneal (i.p.) and intranasal (i.n.) administration of OVA and LPS to induce allergic asthma. On days 18–21, mice received either a low dose (30 mg/kg/day) or high dose (100 mg/kg/day) of DMF via oral gavage according to the experimental group. On day 22, tracheal and lung tissues were isolated. Contractile responses to carbachol, 5 HT, and bradykinin were measured in isolated tracheae using a myograph system. High dose DMF treatment inhibited 5-HT- and bradykinin-induced tracheal contractility. Protein expression of canonical Wnt/β-catenin pathway components (dephosphorylated β-catenin, Wnt-5A/B), NF-κB pathway components (total NF-κB and phosphorylated NF-κB p65), and Nrf2/HO-1 pathway (Nrf2) was assessed in lung tissues by Western blotting. β-catenin levels were significantly reduced in asthmatic mice and the control DMF group, whereas DMF treatment in asthmatic mice maintained expression levels. No significant differences in Wnt-5A levels were observed among groups. Nrf2 levels were decreased in asthmatic mice but were restored following DMF treatment. NF-κB pathway activation in asthmatic mice was inhibited by DMF treatment. Metabolomic analysis of lung tissues revealed that DMF ameliorated asthma-induced disturbances, particularly in glucose metabolism. However, DMF did not significantly affect peribronchial or parenchymal inflammation. Overall, our results indicate that high-dose DMF (100 mg/kg/day) exerts therapeutic effects by improving functional, molecular, and metabolic alterations associated with asthma.