Polygonatum polysaccharide improves cognitive function in senescence-accelerated mice by regulating ferroptosis...

Cognitive decline is a core feature of aging and related neurodegenerative diseases. Polygonatum odoratum, a traditional Chinese medicine used to tonify qi and nourish yin, is a classic herbal remedy for cognitive impairment. Its active component, Polygonatum polysaccharide (POP), exhibits antioxidant and anti-aging potential. Our group's prior research demonstrated that POP could improve age-related cognitive decline. The pathogenesis of cognitive impairment is closely linked to the activation of neuronal ferroptosis, making targeted inhibition of neuronal ferroptosis a highly promising new approach for intervening in cognitive decline. Against this backdrop, whether and how POP suppresses ferroptosis to improve cognitive function warrants attention.

This study aims to elucidate the potential mechanism by which POP mediates the cAMP/PKA/CREB pathway to inhibit ferroptosis and improve cognitive dysfunction in rapidly aging mice.

Six-month-old SAMP8 mice were administered multiple doses of POP. Cognitive function decline improvement in SAMP8 mice was verified by comparing water maze performance and pathological damage across groups, and the optimal dose of POP for cognitive enhancement was determined. Finally, the mechanism by which POP improves cognitive dysfunction in SAMP8 mice was validated using transcriptomics and in vivo experiments.

Behavioral studies and histopathological staining demonstrated that POP significantly reduced the latency period in mice, extended the dwell time in the target quadrant, and increased the number of platform crossings (P < 0.01), thereby enhancing cognitive function in SAMP8 mice. Transcriptomic analysis and in vivo experiments further confirmed that the POP group exhibited decreased expression of Acsl4 and increased expression of Slc7A11 (P < 0.05). Additionally, POP was found to activate the cAMP/PKA/CREB signaling pathway, as evidenced by decreased levels of Fe²⁺ and MDA and significantly increased levels of GSH and SOD (P < 0.05 or P < 0.01), thereby reducing ferroptosis in the brain. Protein docking and co-immunoprecipitation (Co-IP) results indicated a strong affinity between the cAMP pathway and proteins associated with ferroptosis.

This study demonstrates that POP improves cognitive function in SAMP8 mice by mediating the cAMP/PKA/CREB pathway to inhibit ferroptosis. It reveals the potential mechanism of action of POP and further confirms its efficacy in ameliorating age-related cognitive decline.