Polysaccharides from Baihe Dihuang decoction ameliorate depression-like behaviors in rats subjected to chronic unpredictable mild stress through modulation of metabolic homeostasis.

Baihe Dihuang Decoction (BDD) is a traditional Chinese medicinal formula with well-documented antidepressant effects. However, the role of its polysaccharide fraction (BDDP) remains poorly understood. This study aimed to investigate the structural characteristics and antidepressant mechanisms of BDDP through chemical analysis and in vivo validation. BDDP was obtained by ethanol precipitation and analyzed by high-performance anion-exchange chromatography (HPAEC), revealing a heteropolysaccharide composed of rhamnose, arabinose, galactose, glucose, mannose, and fructose, with an average molecular weight of 20.7 kDa and a β-configured glycosidic backbone. In a chronic unpredictable mild stress (CUMS) rat model, BDDP administration significantly alleviated depression-like behaviors and restored monoamine neurotransmitter levels. Integrated proteomic and metabolomic analyses of hippocampal and serum samples indicated that BDDP exerts antidepressant effects primarily through metabolic reprogramming. Key mechanisms include modulation of nitrogen metabolism via CA1/CA3 (which helps rebalance glutamate/GABA and sustain pH homeostasis), enhancement of energy metabolism via branched-chain amino acid catabolism and NAD+ biosynthesis, suppression of neuroinflammation via ω-3/ω-6 fatty acid regulation, and activation of glutathione-mediated antioxidant defense. These findings show that BDDP acts as a multi-target macromolecular therapeutic candidate for depression and links its structural features to systemic metabolic regulation.