College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun 130118, China.
Looking Up Starry Sky Medical Research Center, Siping 136001, China.
Phytomedicine. 2022 Sep;104:154341. doi: 10.1016/j.phymed.2022.154341. Epub 2022 Jul 16.
Aging is an inevitable gradual process of the body, which can cause dysfunction or degeneration of the nervous or immune system, thus becoming a critical pathogenic factor inducing neurodegenerative diseases. Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C.A. Meyer exerted obvious memory-enhancing and anti-aging effects, and the simpler the structure of ginsenosides, the better the biological activity. Ginsenoside Rg2 (Rg2) is a prominent and representative panaxatriol-type ginsenoside produced during ginseng processing, which has been reported to have pretty good neuroprotective activity.
The work was aimed at exploring the therapeutic effects and possible molecular mechanisms of Rg2 by establishing the subacute brain aging model induced by D-galactose (D-gal) in mice.
The anti-aging activity of G-Rg2 (10, 20 mg/kg for 4 weeks) was assessed using the D-gal induced brain aging model (800 mg/kg for 8 weeks). The Morris water maze (MWM) and histopathological analysis were used to evaluate the cognitive function and pathological changes of the brain in mice, respectively. The protein expression levels of p53, p21, p16ink4α, IL-6, CDK4, ATG3, ATG5, ATG7, LC3, p62, LAMP2, and TFEB were quantified through western blot analysis. The degree of mitochondrial damage and the number of mitochondrial autophagolysosomes in hippocampal neurons were monitored using TEM analysis.
The results showed that Rg2 could significantly restore D-gal-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Rg2 treatment also considerably decreased the over-expression of aging-related proteins such as p53/p21/p16ink4α induced by D-galactose, which demonstrated that Rg2 possessed good anti-aging activity. Meanwhile, Rg2 could evidently reduce the pathological changes caused by D-gal exposure. Moreover, the results from transmission electron microscopy and western blot analysis indicated that Rg2 could delay the brain aging induced by D-gal in mice via promoting the degradation of the autophagy substrate p62 while increasing the protein expression level of LAMP2/TFEB to maintain mitochondrial function.
These results indicate that Rg2 could postpone brain aging by increasing mitochondrial autophagy flux to maintain mitochondrial function, which greatly enriched the research on the pharmacological activity of ginsenosides for delaying brain aging.
衰老是机体不可避免的渐进过程，可导致神经或免疫系统功能障碍或退化，从而成为诱导神经退行性疾病的关键致病因素。先前的报道已经证实，来源于人参 Panax ginseng. C.A. Meyer 的皂苷（人参皂苷）具有明显的增强记忆和抗衰老作用，且人参皂苷的结构越简单，生物活性越好。人参皂苷 Rg2（Rg2）是一种在人参加工过程中产生的突出且具有代表性的人参三醇型皂苷，据报道其具有很好的神经保护活性。
本工作旨在通过建立 D-半乳糖（D-gal）诱导的小鼠亚急性脑衰老模型，探讨 Rg2 的治疗作用及可能的分子机制。
采用 D-gal 诱导的脑衰老模型（8 周，800mg/kg），评估 G-Rg2（10、20mg/kg，连续 4 周）的抗衰老活性。使用 Morris 水迷宫（MWM）和组织病理学分析分别评估小鼠的认知功能和脑内病理变化。通过 Western blot 分析定量检测 p53、p21、p16ink4α、IL-6、CDK4、ATG3、ATG5、ATG7、LC3、p62、LAMP2 和 TFEB 的蛋白表达水平。通过 TEM 分析监测海马神经元中线粒体损伤程度和线粒体自噬溶酶体的数量。
结果表明，Rg2 可显著恢复 D-gal 诱导的小鼠记忆功能障碍、胆碱能功能障碍和氧化还原系统失衡。Rg2 处理还显著降低了 D-半乳糖诱导的衰老相关蛋白（如 p53/p21/p16ink4α）的过度表达，表明 Rg2 具有良好的抗衰老活性。同时，Rg2 可明显减轻 D-gal 暴露引起的病理变化。此外，透射电镜和 Western blot 分析结果表明，Rg2 可通过促进自噬底物 p62 的降解，同时增加 LAMP2/TFEB 的蛋白表达水平来维持线粒体功能，从而延缓 D-gal 诱导的小鼠脑衰老。
这些结果表明，Rg2 通过增加线粒体自噬通量来维持线粒体功能，从而延缓大脑衰老，这极大地丰富了人参皂苷在延缓大脑衰老方面的药理活性研究。
