Ginsenoside Rc mitigates hippocampal neuronal damage and cognitive impairment in vascular dementia rats via the pY705-Stat3/Foxo3a and pS727-Stat3/GRIM-19 pathways
Yuying Wu, Zhizhen Zhang, Xiao‐Yuan Lian
Abstract
ABSTRACT Background Vascular dementia (VaD), the second most common cause of dementia, lacks effective treatments. Ginsenoside Rc (GRc) has demonstrated therapeutic potential, but its role in VaD remains unclear. This study investigates the protective effects of GRc in VaD and its underlying mechanisms. Methods Cognitive function was assessed using novel object recognition and Morris water maze tests. Neuronal and glial status in the cortex and hippocampus were evaluated by immunohistochemistry, Nissl staining, immunofluorescence, transmission electron microscopy, and Western blotting. Drug target identification was performed through molecular docking, molecular dynamics simulations, and cellular thermal shift assay. Apoptosis markers, along with pY705-Stat3/Foxo3a/Nrf2 and pS727-Stat3/GRIM-19/Sirt1/PGC1α pathway-related factors, were analyzed by cell viability assay, Western blotting, immunoprecipitation, and commercial assay kits. Results GRc ameliorated cognitive deficits in VaD rats, attenuating synaptic disruption and neuronal apoptosis in the hippocampal CA1 region. GRc bound to Stat3 and promoted its phosphorylation at Y705 and S727. It further enhanced catalase and SOD activity through pY705-Stat3-mediated Foxo3a activation and upregulated GSR, Gpx4, and GSH via the Nrf2 pathway. Moreover, GRc stabilized the pS727-Stat3/GRIM-19 complex, facilitating mitochondrial translocation of pS727-Stat3, which enhanced mitochondrial Complex I and II activities, increased NAD + levels, and activated the Sirt1/PGC1α pathway, promoting mitochondrial biogenesis and ATP production. Conclusion GRc exerted neuroprotective effects in VaD by targeting Stat3 and driving its dual-phosphorylation. Through the pY705-Stat3/Foxo3a and pS727-Stat3/GRIM-19 pathways, GRc alleviated hippocampal neuronal apoptosis and synaptic dysfunction, thereby improving cognitive function in VaD rats.