Gypenosides alleviate oxidative stress in the hippocampus, promote mitophagy, and mitigate depressive-like behaviors induced by CUMS via SIRT1.

ETHNOPHARMACOLOGICAL RELEVANCE

The use and efficacy of Gynostemma [Gynostemma pentaphyllum (Thunb.) Makino], a versatile traditional Chinese herb, was first documented in the renowned pharmacopoeia, "Compendium of Materia Medica". Gypenosides (Gps), saponin components are the primary constituents responsible for its biological activities and clinical effects, which include antioxidant, immunoregulatory, antitumor, and neuroprotective properties. Pharmacological studies have shown that Gps has the potential to combat depression. However, the exact molecular mechanisms underlying its antidepressant effects remain unclear.

AIM OF THE STUDY

This study aims to elucidate the mechanisms underlying the antidepressant effects of Gps through antioxidative stress, utilizing an integrated approach that includes network pharmacology, molecular simulations, and experimental validation.

MATERIALS AND METHODS

Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) and were orally administered doses of Gps (50 and 100 mg/kg) and fluoxetine (10 mg/kg). The regulatory effects of Gps on depression-like behaviors in CUMS rats and their impact on oxidative stress levels in the hippocampus region were evaluated. Network pharmacology was used to investigate the mechanisms by which Gps affects oxidative stress in depression, and was accompanied by molecular docking and dynamics simulations. CUMS rats were treated orally with Gps (100 mg/kg) and injected with EX527 for rescue experiments to validate the role of SIRT1 in antioxidative stress and evaluate the impact of Gps on mitophagy.

RESULTS

Gps ameliorated depression-like behaviors induced by CUMS in rats. The improvements observed included an increased sucrose preference, reduced immobility time in the tail suspension and forced swim tests, and an increased movement distance in the open-field test. Additionally, Gps effectively reduced reactive oxygen species, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine levels in the hippocampus, while increasing the contents of ATP, catalase, superoxide dismutase, and glutathione, indicating an increased capacity for antioxidative stress in the hippocampus. Furthermore, Gps increased the number of neuronal cells in the hippocampal CA1 region and the level of mitochondrial autophagy, with SIRT1 as a potential key target. Inhibition of SIRT1 expression by exposure to EX527 reversed the beneficial effects of Gps, further validating the critical role of SIRT1 in the regulation of oxidative stress and improving depression-like behavior.

CONCLUSION

Gps improved the antioxidative stress capacity of the hippocampus and promoted mitophagy in CUMS rats through SIRT1, thus protecting hippocampal neurons and improving depression-like behavior.