College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China.
College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China; College of Life Sciences, Jilin Agricultural University, Changchun 130118, PR China.
Phytomedicine. 2024 Dec;135:156063. doi: 10.1016/j.phymed.2024.156063. Epub 2024 Sep 16.
Damage to the blood-brain barrier (BBB) is vital for the development of Alzheimer's disease (AD). Ginsenoside Rg2 (G-Rg2) has been shown to improve a variety of brain injuries, but whether G-Rg2 can improve the BBB leakage related to AD is still unclear.
Illuminate the effect and mechanism of G-Rg2 on AD-related BBB damage. To clarify the role of G-Rg2 in Toll-like receptor pathway and oxidative stress pathway and its effect on tight junction proteins (TJs) expression in vivo and in vitro experiments.
In our research, the tightness of the BBB was improved and the inflammatory pathway was suppressed after 4 weeks of treatment with G-Rg2 (10 mg kg and 20 mg kg) in aluminum trichloride (AlCl) plus d-galactose (D-gal) caused AD mice (p < 0.05; p < 0.01). Concurrently, the stability of TJs in mouse brain endothelial cells (bEnd3) was improved after okadaic acid (OA) -induced AD model cells were pretreated with G-Rg2 (5 μM, 10 μM, and 20 μM) for 24 h (p < 0.05; p < 0.01). The oxidative stress pathway and Toll-like receptor pathway in mouse astrocyte-cerebellum (MA-c) were inhibited (p < 0.05; p < 0.01). Meanwhile, in vitro interaction model results showed that G-Rg2 reduced the activation of MA-c, thereby alleviating the degradation of TJs in bEnd3 (p < 0.05; p < 0.01). The co-culture system of MA-c and bEnd3 further clearly demonstrated that G-Rg2 (20 μM) could improve their interaction and enhance BBB tightness.
This study suggests that G-Rg2 can inhibit the TLR4/MyD88/MMP9 inflammatory pathway by reducing the activation of MA-c and the binding of TLR4 to MyD88, thereby decreasing the secretion of inflammatory factors and matrix metalloproteinases (MMPs), hence maintaining the stability of TJs in bEnd3, which may be one of the mechanisms of G-Rg2 in reducing AD-related BBB damage.
血脑屏障（BBB）的损伤对阿尔茨海默病（AD）的发展至关重要。已证实人参皂苷 Rg2（G-Rg2）可改善多种脑损伤，但 G-Rg2 是否能改善与 AD 相关的 BBB 渗漏尚不清楚。
阐明 G-Rg2 对 AD 相关 BBB 损伤的作用及机制。通过体内和体外实验，阐明 G-Rg2 在 Toll 样受体通路和氧化应激通路中的作用及其对紧密连接蛋白（TJs）表达的影响。
在我们的研究中，用 G-Rg2（10 mg kg 和 20 mg kg）治疗铝三氯化物（AlCl）加半乳糖（D-gal）引起的 AD 小鼠 4 周后，BBB 的紧密性得到改善，炎症通路受到抑制（p<0.05;p<0.01）。同时，用 G-Rg2（5 μM、10 μM 和 20 μM）预处理 okadaic 酸（OA）诱导的 AD 模型细胞 24 h 后，小鼠脑内皮细胞（bEnd3）中 TJ 的稳定性得到改善（p<0.05;p<0.01）。用 G-Rg2 预处理后，抑制了小鼠星形细胞-小脑（MA-c）中的氧化应激通路和 Toll 样受体通路（p<0.05;p<0.01）。同时，体外相互作用模型结果表明，G-Rg2 降低了 MA-c 的激活，从而减轻了 bEnd3 中 TJ 的降解（p<0.05;p<0.01）。MA-c 和 bEnd3 的共培养系统进一步清楚地表明，G-Rg2（20 μM）可以改善它们的相互作用，增强 BBB 的紧密性。
本研究表明，G-Rg2 通过降低 MA-c 的激活和 TLR4 与 MyD88 的结合，抑制 TLR4/MyD88/MMP9 炎症通路，减少炎症因子和基质金属蛋白酶（MMPs）的分泌，从而维持 bEnd3 中 TJ 的稳定性，这可能是 G-Rg2 减轻 AD 相关 BBB 损伤的机制之一。
