Astragaloside IV Confers Prophylactic Efficacy Against Depression Associated with the ROS/Nrf2/Keap1 Axis: Modulation of Oxidative Stress and Energy Homeostasis.

Abstract

Aims: Depression is a prevalent mood disorder with significant suffering and heightened suicide risk. Accumulating evidence points to oxidative stress and impaired energy metabolism of the brain as key contributors to the pathogenesis of depression. Astragaloside IV (AIV) has been demonstrated to alleviate neurological damage. The capacity of AIV for antioxidation has also been gradually discovered. Yet, it still just scratches the surface of the antidepression mechanisms of AIV. Our aim was to explore a novel mechanism of action of AIV from the perspectives of redox homeostasis and energy metabolism via the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) axis.

Results: AIV ameliorated anxiety and cognitive dysfunction in rats with depression-like behaviors. Furthermore, we illustrated that AIV reversed redox dyshomeostasis of rats with depression-like behaviors in terms of decreasing the level of malondialdehyde while increasing the abundances of catalase, superoxide dismutase, and glutathione peroxidase. In addition, AIV significantly increased the levels of indicators of energy metabolism that were interrupted by depression. Furthermore, in vitro, AIV significantly increased the levels of indicators related to the Nrf2/Keap1 signaling pathway in corticosterone-induced PC12 cells.

Innovation: For the first time, it demonstrates that AIV alleviates depression by modulating the ROS/Nrf2/Keap1 axis and restoring hippocampal energy metabolism in a chronic unpredictable mild stress model.

Conclusion: The current findings not only offer novel insights into antidepressant-like effects of AIV through the ROS/Nrf2/Keap1 axis but also provide a foundation for enhancing clinical efficiency and enriching drug selection. Antioxid. Redox Signal. 44, 822-842.