Cycloastragenol Provides Pharmacokinetic Advantages over Astragaloside IV with Enhanced Cochlear Exposure and Protection Against Age-Associated Hearing Dysfunction

Background: Adequate inner-ear exposure is a key challenge in treating age-related hearing loss (ARHL). Astragaloside IV (AS-IV), the principal saponin of Astragalus membranaceus, has anti-aging activity but poor oral bioavailability; its aglycone cycloastragenol (CAG) may represent a pharmacokinetically optimized active moiety. Methods: We compared the pharmacokinetics, cochlear exposure, and biotransformation of CAG and AS-IV after oral dosing in mice by LC-MS/MS, and evaluated CAG in a D-galactose-induced accelerated-aging rat model (ABR, hair-cell morphology, redox and cytokine assays) and in D-galactose-stressed HEI-OC1 cells. Results: CAG achieved markedly higher plasma and perfused whole-cochlea exposure than intact AS-IV after equivalent dosing, even after molar-dose normalization. AS-IV was biotransformed to CAG in vivo and in liver microsomes, supporting CAG as a quantitatively important active metabolite. In rats, oral CAG reduced ABR threshold elevation and preserved hair-cell architecture, improved cochlear redox status (higher SOD/GSH; lower ROS/MDA), and lowered serum TNF-α/IL-6. In HEI-OC1 cells, CAG attenuated mitochondrial membrane-potential loss and apoptosis. Conclusions: At equimolar concentrations, CAG and AS-IV showed comparable protective activity in vitro, indicating that the advantage of CAG resides mainly in its pharmacokinetic profile. CAG thus attenuates auditory dysfunction in an accelerated-aging model with superior exposure, supporting its further development for age-associated hearing disorders.