Anti-Inflammatory Effects of Ginsenoside Rg1 and Low-Dose Ginseng Extract in an Astrocyte-Microglia Co-Culture Model of Inflammation

Background: Neuroinflammation contributes to etiopathology and symptom severity in neurodegenerative and neuropsychiatric disorders. Glial cells, especially microglia and astrocytes, play a crucial role in neuroinflammation. It has been reported that ginseng and its bioactive component ginsenoside Rg1 exhibit anti-inflammatory effects and improve cognitive performance in various models. However, the exact underlying mechanisms remain unclear. Methods: An astrocyte-microglia co-culture model simulating physiological (M5, 5-10% microglia) and pathological/inflammatory (M30, 30-40% microglia) conditions was treated with different concentrations of ginsenoside Rg1 (15, 30, 45 µM), ginseng extract (derived from Korean red ginseng) at low-dose (12.5, 25, 37.5 µg/ml) or high-dose (125, 250, 375 µg/ml) for 24 hours. Cell viability was assessed by MTT assay. Microglial reactivity was examined by immunocytochemistry. Astrocytic gap-junctional coupling was investigated using scrape loading method and connexin 43 (Cx43) expression was analyzed by immunocytochemistry and Western blot. Results: Both Rg1 and low-dose ginseng extract reduced microglial activation under inflammatory conditions by promoting a phenotypic shift from activated to homeostatic (resting) microglia. Rg1 preserved astrocytic gap-junctional function by preventing the inflammation-induced downregulation of Cx43 expression and enhancing Cx43-mediated gap-junctional intercellular communication. Rg1 caused a significant reduction of glial cell viability only at high concentrations (30 and 45 µM) under inflammatory conditions. High-dose ginseng extract showed significant concentration-dependent cytotoxicity, reducing glial cell viability under physiological and pathological conditions, without comparable anti-inflammatory benefits. Conclusions: This study suggests that low-dose ginseng and its active compound Rg1 exert anti-inflammatory effects by modulation of astrocytic coupling and microglial reactivity. These results provide a novel therapeutic perspective for ginseng in the treatment of neurodegenerative and neuropsychiatric diseases related to neuroinflammation.