Radix Hedysari Polysaccharides modulate the gut-brain axis and improve cognitive impairment in SAMP8 mice

Radix Hedysari Polysaccharides (RHP) are the principal bioactive constituents of the traditional Chinese medicinal herb Radix Hedysari. This study aims to evaluate the neuroprotective effects of RHP in both cellular and animal models of Alzheimer's disease (AD) and to elucidate the underlying molecular mechanisms.

HT22 cells subjected to Aβ_25-35-induced cytotoxicity were pretreated with RHP, followed by assessments of reactive oxygen species (ROS) generation, mitochondrial superoxide (mSOX) levels, and mitochondrial membrane potential (ΔΨm). Senescence-accelerated mouse-prone 8 (SAMP8) mice were orally administered RHP for 12 weeks. Behavioral assays were conducted to assess cognitive function, while metabolomic and proteomic analyses were performed to examine serum metabolic alterations and hippocampal protein expression profiles. Additionally, neuronal autophagy and gut barrier integrity were evaluated using immunohistochemistry, transmission electron microscopy, and biomarker quantification.

RHP treatment significantly attenuated Aβ_25-35-induced oxidative stress in HT22 cells by reducing ROS and mSOX production while preserving ΔΨm. In SAMP8 mice, RHP improved cognitive performance, preserved hippocampal mitochondrial ultrastructure, and enhanced neuronal autophagic activity. Moreover, RHP modulated serum metabolic pathways and alleviated gut barrier dysfunction, suggesting a role in gut-brain axis regulation.

RHP ameliorates cognitive impairment in SAMP8 mice, potentially through its modulation of systemic metabolism, mitigation of neuronal mitochondrial damage, and restoration of gut barrier integrity. These findings highlight the therapeutic potential of RHP in AD intervention and warrant further investigation into its mechanistic underpinnings.