Lung-Targeted Delivery of Nebulized α‑Asaronol Attenuates Airway Inflammation and Hyperresponsiveness in Murine Asthma Models.

Acorus tatarinowii, a traditional Chinese medicinal herb, is used clinically to treat neurological and respiratory disorders. Our previous work showed that α-asaronol (α-AOL), a low-toxicity natural constituent of A. tatarinowii, exerts robust antiepileptic effects through γ-aminobutyric acid (GABA)-ergic modulation. Given the critical role of the peripheral GABAergic system in asthma pathogenesis and inflammation regulation, the therapeutic potential of α-AOL for asthma warrants investigation. This study evaluated the efficacy, safety, and pulmonary targeting of both nebulized and oral α-AOL. Murine asthma models were established using ovalbumin (OVA) and house dust mite (HDM). Both nebulized α-AOL (5, 10, 20 mg/kg) and oral α-AOL were administered, with α-asarone, and albuterol as references. Histological, biochemical, and functional assessments were performed to evaluate lung inflammation, mucus secretion, cytokine levels (IL-4, IL-5, IL-13, TNF-α), airway smooth muscle (ASM) relaxation, and airway hyperresponsiveness (AHR). Pharmacokinetic and safety profiles were determined via HPLC tissue distribution analysis, human ether-à-go-go related gene (hERG) assays, and monitoring of respiratory and cardiovascular function. Nebulized α-AOL dose-dependently alleviated OVA/HDM-induced airway inflammation, characterized by reduced inflammatory cell infiltration, cytokine release, mucus hypersecretion, and AHR. It also induced concentration-dependent ASM relaxation and demonstrated dual therapeutic activity by both preventing and reversing methacholine (Mch)-induced acute bronchospasm. Nebulization provided sustained lung targeting (≥60 min retention). α-AOL exhibited negligible hERG inhibition (IC50 > 100 μM), no adverse respiratory effects, and no significant impact on blood pressure. In conclusion, nebulized and oral α-AOL possesses potent anti-inflammatory and bronchodilatory activities; the nebulized formulation shows favorable lung-targeted delivery and an excellent safety profile, positioning it as a promising inhaled candidate for asthma therapy, particularly in pediatric populations.