Panacis Quinquefolii Radix Polysaccharides Alleviate Depressive-Like Behaviors in Chronic Unpredictable Mild Stress-Induced Mice by Suppressing Complement C1Q/C3-Mediated Microglial Synaptic Pruning and Modulating Gut Microbiota

Mengjun Xie; Lingling Feng; Ruyi Li; Mengqi Li; Liang Shen; Minghui Zhang; Yutong Wei; Qiao Yin; Datong Wang; Liqing Chen; Kai Song; Peipei Wang; Qifei Cong

doi:10.1002/cns.70859

Panacis Quinquefolii Radix Polysaccharides Alleviate Depressive-Like Behaviors in Chronic Unpredictable Mild Stress-Induced Mice by Suppressing Complement C1Q/C3-Mediated Microglial Synaptic Pruning and Modulating Gut Microbiota

CNS Neurosci Ther. 2026 Apr;32(4):e70859. doi: 10.1002/cns.70859.

Authors

Mengjun Xie^{1

2}, Lingling Feng^{1

2}, Ruyi Li³, Mengqi Li^{1

2}, Liang Shen^{1

2}, Minghui Zhang³, Yutong Wei^{1

2}, Qiao Yin⁴, Datong Wang^{1

2}, Liqing Chen⁵, Kai Song², Peipei Wang³, Qifei Cong^{1

2

4

6

7

8}

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.
² Department of Nephrology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
³ Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.
⁴ Department of Neurology, Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, China.
⁵ Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
⁶ School of Life Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China.
⁷ Institute of Neurological Diseases, Soochow University-Suzhou Blue Cross Brain Hospital, Soochow University, Suzhou, China.
⁸ Biomedical Basic Research Center of Jiangsu, Soochow University, Suzhou, China.

Abstract

Aims: Panax quinquefolius Radix (American ginseng) is a medicinal herb used for its neuroprotective and tonic effects. However, the antidepressant potential of its polysaccharide components is not well studied. This research aimed to investigate the antidepressant effects of XYS1, a polysaccharide from American ginseng, focusing on mechanisms related to the complement system and the gut-brain axis.

Methods: A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive behaviors. Mice were treated with XYS1 via oral gavage, followed by assessments of behavior, molecular changes, and gut microbiota.

Results: XYS1 treatment significantly alleviated depression-like behaviors in CUMS mice, as demonstrated by reduced immobility time in the TST and FST, and increased sucrose preference and body weight. Mechanistically, XYS1 attenuated complement system activation by downregulating C1Q expression in microglia and C3 expression in astrocytes, not only in the hippocampal CA1 region but also in the mPFC and PVN, as well as in the colon. Furthermore, XYS1 inhibited microglial activation and associated synaptic phagocytosis, preserved glutamatergic neuron density, restored excitatory synapse density, and reversed CUMS-induced gut microbiota dysbiosis by enriching Bacillota and reducing Bacteroidota abundance. Additionally, XYS1 effectively mitigated both colonic and systemic inflammation, reducing pro-inflammatory cytokines TNF-α and IL-1β and complement components C1Q and C3, while restoring anti-inflammatory IL-10 levels, thereby modulating the gut-brain axis.

Conclusions: XYS1 exerts antidepressant effects by modulating the C1Q/C3 complement pathway, inhibiting microglial-mediated synaptic pruning, and restoring gut microbiota homeostasis.

Keywords: Panacis Quinquefolii Radix; chronic unpredictable mild stress; complement; gut microbiota; microglia; polysaccharide.

MeSH terms

Animals
Antidepressive Agents* / pharmacology
Complement C1q* / metabolism
Complement C3* / antagonists & inhibitors
Complement C3* / metabolism
Depression* / drug therapy
Depression* / metabolism
Gastrointestinal Microbiome* / drug effects
Gastrointestinal Microbiome* / physiology
Male
Mice
Mice, Inbred C57BL
Microglia* / drug effects
Microglia* / metabolism
Neuronal Plasticity* / drug effects
Neuronal Plasticity* / physiology
Panax*
Polysaccharides* / pharmacology
Polysaccharides* / therapeutic use
Stress, Psychological* / drug therapy
Stress, Psychological* / metabolism
Stress, Psychological* / psychology

Substances

Polysaccharides
Complement C1q
Complement C3
Antidepressive Agents

Abstract

MeSH terms

Substances

Grants and funding