The protective effects and mechanisms of Polygonatum sibiricum polysaccharides in chronic stress-induced neural damage

Xiangfei Zhang; Danyang Wang; Yupei Liu; Jing Sun; Bei Fan; Fengzhong Wang; Cong Lu

doi:10.1016/j.jep.2025.120219

The protective effects and mechanisms of Polygonatum sibiricum polysaccharides in chronic stress-induced neural damage

J Ethnopharmacol. 2025 Jun 28:352:120219. doi: 10.1016/j.jep.2025.120219. Online ahead of print.

Authors

Xiangfei Zhang¹, Danyang Wang¹, Yupei Liu¹, Jing Sun¹, Bei Fan², Fengzhong Wang³, Cong Lu⁴

Affiliations

¹ Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China.
² Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China. Electronic address: fanbei517@163.com.
³ Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China. Electronic address: wangfengzhong@sina.com.
⁴ Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China. Electronic address: lucong198912@126.com.

PMID: 40588146
DOI: 10.1016/j.jep.2025.120219

Abstract

Ethnopharmacological relevance: Polygonatum sibiricum (PS) has a long-standing history of application in traditional Chinese medicine and various ethnic pharmacopeias to treat fatigue, aging-related weakness, memory decline, and metabolic disorders. It is believed to "tonify Qi and Yin," "nourish the kidney and spleen," and enhance vitality. Recent pharmacological studies have confirmed its antioxidant, neuroprotective, and anti-aging properties, suggesting its potential in improving cognitive impairment and neural damage, particularly under chronic stress or degenerative conditions. However, its mechanisms in memory-related disorders remain underexplored.

Aim of the study: This study aims to investigate the protective effects and underlying mechanisms of Polygonatum sibiricum polysaccharides (PSP) against neuronal damage induced by chronic stress. Specifically, the study evaluates the efficacy of PSP in ameliorating cognitive dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances in mouse models of chronic sleep disturbance (CSD) and chronic restraint stress (CRS). This research focuses on exploring the neuroprotective potential and underlying biological mechanisms of Polygonatum sibiricum polysaccharides (PSP) in response to neuronal injury caused by chronic stress. Specifically, the study evaluates the efficacy of PSP in ameliorating cognitive dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances in mouse models of CSD and CRS.

Materials and methods: We developed chronic stress animal models by employing CSD and CRS. The ameliorative effects of PSP on stress-induced neuronal injury were assessed using a series of behavioral tests. Biochemical and histological assessments were conducted to investigate how PSP modulates oxidative stress, neuroinflammatory responses, and neurotransmitter homeostasis.

Results: PSP exert comprehensive neuroprotective effects in mice exposed to chronic stress, acting through multiple interconnected mechanisms. In behavioral assessments, PSP significantly improved cognitive performance in both CSD and CRS models. Mice treated with PSP showed shorter escape latency and more frequent platform crossings in the MWM, indicating enhanced spatial learning and memory. Similarly, improved outcomes in the NOR and OLR tests reflected better recognition and spatial memory, while performance gains in the OFT and ST suggested reduced anxiety-like behavior and improved associative learning. These behavioral enhancements were supported by marked reductions in hippocampal interleukin-6 (IL-6) and interleukin-1β (IL-1β) levels in CSD-treated mice, indicating potent anti-inflammatory activity. PSP also modulated neurotransmitter balance by increasing acetylcholine (ACh), critical for learning and memory, and decreasing γ-aminobutyric acid (GABA), which is often elevated under stress and associated with impaired cognition. PSP enhanced the antioxidant capacity in CRS mice, as evidenced by elevated activities of superoxide dismutase (SOD) and catalase (CAT) enzymes and a concurrent reduction in malondialdehyde (MDA) concentration, thereby protecting neurons from oxidative damage. Moreover, PSP reduced serum corticosterone (CORT) levels, reflecting its regulatory influence on the hypothalamic-pituitary-adrenal (HPA) axis and mitigating glucocorticoid-driven hippocampal impairment commonly associated with chronic stress. Collectively, these findings reveal that PSP not only alleviates behavioral deficits but also targets the underlying biochemical and hormonal disruptions caused by chronic stress, highlighting its therapeutic potential in preventing or treating stress-related cognitive disorders.

Conclusion: This study demonstrates that PSP exert notable neuroprotective effects in chronic stress models by improving cognitive function, reducing oxidative stress and neuroinflammation, balancing neurotransmitter levels, and regulating HPA axis activity. These findings provide pharmacological support for the traditional use of PS in treating neurodegenerative and stress-related cognitive disorders.

Keywords: Chronic restraint stress; Chronic sleep disturbance; Cognitive impairment; Neuroinflammation; Oxidative stress; Polygonatum sibiricum polysaccharides.