Tetrandrine Alleviates Allergic Rhinitis via REV-ERBα-Dependent Acetylcholine

Allergic rhinitis is a prevalent chronic inflammatory disorder of the nasal mucosa, imposing substantial medical and socioeconomic burdens. Thus, there is an urgent need to develop novel agents capable of both symptom relief and immune modulation. This study elucidates the mechanism by which tetrandrine alleviates allergic rhinitis through REV-ERBα activation and cholinergic pathway suppression. In ovalbumin-induced allergic rhinitis mice, intranasal tetrandrine significantly reduced sneezing frequency and nasal scratching versus controls, while decreasing serum histamine and substance P levels. Mechanistically, tetrandrine dose-dependently upregulated the mRNA and protein expression of REV-ERBα in nasal mucosa, enhancing its transcriptional repression in Gal4 reporter assays. Genetic ablation of Rev-erbα abolished tetrandrine's efficacy, exacerbating allergic rhinitis symptoms and inflammatory mediators. Crucially, tetrandrine suppressed choline acetyltransferase expression in nasal mucosa, reducing the level of acetylcholine; this effect was diminished by α-NETA (choline acetyltransferase inhibitor) pretreatment. This confirmed the essential role of REV-ERBα-dependent suppression of choline acetyltransferase-mediated acetylcholine synthesis in tetrandrine's therapeutic effect on allergic rhinitis. These findings establish tetrandrine as a novel agent targeting the circadian clock pathway and the circadian-allergy crosstalk, providing a new therapeutic strategy for allergic rhinitis.