Asperosaponin VI enhances stress resilience by activating hippocampal neural stem cells

Enhancing stress resilience through hippocampal neural stem cell (NSC) activation is a promising way to reduce depression risk. Earlier studies show that asperosaponin Ⅵ (ASA-VI) can efficiently cross the blood-brain barrier and provide neuroprotective benefits, but its role in activating NSC and improving stress resilience has not been explored.

This study aims to explore the therapeutic potential and molecular mechanisms of ASA-VI in enhancing stress resilience through hippocampal NSC activation.

We compared the hippocampal neurogenesis between high-stress resilience (HSR) mice and low-stress resilience (LSR) mice using immunohistochemistry, and explored the role of neurogenesis in maintaining stress resilience by inhibiting NSC activation with temozolomide. We evaluated the effect of ASA-VI on NSC proliferation and differentiation using both in vitro and in vivo investigations. Comprehensive methodologies, including hippocampal transcriptome analysis, western blotting, immunolocalization and pharmacological blocker treatment, were utilized to identify the involvement of the PI3K/Akt pathway in ASA-VI activating NSC.

HSR mice had more Ki67⁺-GFAP⁺ cells, BrdU⁺-DCX⁺ cells, and BrdU⁺-NeuN⁺ cells in hippocampus than LSR mice. Inhibiting NSC activation with temozolomide reduced stress resilience and worsened depressive symptoms in CMS-exposed mice. We also found that ASA-VI strongly promoted NSC proliferation and neuronal differentiation in vitro. In CMS mice, ASA-VI prevented stress-induced impairments in neurogenesis at all stages, from NSC activation to neuron maturation. Consequently, ASA-VI significantly increased the proportion of stress-resilient mice and alleviated depressive-like behaviors. Transcriptomic and biochemical analyses revealed that ASA-VI activates the PI3K/Akt signaling pathway in NSC. Notably, the pro-neurogenic and resilience-enhancing effects of ASA-VI were eliminated by the PI3K inhibitor LY294002.

Our findings identify ASA-VI as a novel agent that enhances stress resilience and prevents depression by activating the PI3K/Akt pathway in NSC.