Stereoselective neuroprotective activity and blood-brain barrier permeability of Schisandrin B enantiomers

Schisandrin B (Sch B), a major dibenzocyclooctadiene lignan from Schisandra chinensis, possesses a unique form of axial chirality and exhibits significant neuropharmacological properties. To address the formidable analytical challenge of resolving this rigid axial chiral scaffold in complex biological environments, a high-performance chiral HPLC platform was systematically developed. Superior resolution (Rs = 2.93) was achieved on a Chiralcel OD-RH column using a methanol-water (90:10, v/v) mobile phase. By coupling experimental optimization with molecular docking simulations, the separation mechanism was elucidated, revealing that specific hydrogen bonding and π-σ hydrophobic interactions between the cellulose-based chiral stationary phase (CSP) and the axial chiral framework are the primary driving forces for stereoselective recognition. To overcome the matrix-resolution trade-off, the method was optimized to ensure high sensitivity and minimal Ion Suppression in five distinct biological matrices, including lipid-rich brain tissue. Under multiple reaction monitoring (MRM) mode, the analytes were measured with high specificity (m/z 401.2→285.2). This robust analytical platform was then applied to investigate the stereoselective blood-brain barrier permeability and neuroprotective efficacy of Sch B. While R-Sch B showed superior antioxidant efficacy in PC12 cells, S-Sch B exhibited significantly higher brain-to-plasma ratios (2.31 vs. 1.49) and preferential central nervous system accumulation. These findings, facilitated by enantiomer-specific interactions with efflux transporters such as P-glycoprotein, highlight the critical role of chirality in drug disposition and provide a reliable analytical framework for the development of enantiomer-specific neuroprotective agents.