Evaluating the effects of mitochondrial autophagy flux on ginsenoside Rg2 for delaying D-galactose induced brain aging in mice

Background: 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. Purpose: 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. Methods: 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, p16ink4 alpha, 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. Results: 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/p16ink4 alpha 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. Conclusion: 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.