Rhodiola sacra Protects Against Hippocampal Neuronal Apoptosis inChronic Cerebral Ischemia via SIRT1-Driven Mitochondrial Biogenesis

Introduction: Chronic cerebral ischemia (CCI) induces hippocampal neuronal injury, with mitochondrial dysfunction emerging as a pivotal pathological driver of ischemic brain damage. Enhancing mitochondrial biogenesis (MB) represents a promising reparative strategy to restore neuronal homeostasis. Rhodiola sacra (RS), a traditional Tibetan herb, exhibits neuroprotective potential against ischemic injury; however, its underlying mechanisms, particularly its association with MB, remain unclear. This study aims to investigate the protective effects of RS on neuronal apoptosis and mitochondrial dysfunction in CCI rats and oxygen-glucose deprivation (OGD)-exposed cells, with a focus on elucidating the role of SIRT1 in mediating these effects. Methods: The CCI rat model was established through bilateral common carotid artery occlusion. Spatial learning and memory abilities were evaluated using the Morris water maze. Hippocampal neuronal apoptosis was assessed via TUNEL staining, and mitochondrial damage was examined using transmission electron microscopy. Flow cytometry was employed to detect cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels. Immunofluorescence staining was used to visualize the mitochondrial permeability transition pore (mPTP). Intracellular ATP levels were measured using a luminol-based chemiluminescence assay, and mitochondrial DNA (mtDNA) content was quantified by qPCR. Additionally, small interfering RNA (siRNA) was utilized to verify the critical role of SIRT1 in mediating the protective effects. Results: RS significantly improved spatial learning and memory, attenuated hippocampal neuronal apoptosis, and increased mitochondrial content in CCI rats. In SH-SY5Y cells exposed to OGD, salidroside, a key active component of RS, reduced apoptosis and restored mitochondrial function, as evidenced by elevated MMP, ATP, and mtDNA levels, along with suppressed ROS and mPTP activity. Mechanistically, salidroside upregulated SIRT1 expression, which correlated with enhanced MB markers. Notably, inhibition of SIRT1 abolished the anti-apoptotic effects and MB activation induced by salidroside. Discussion: These findings highlight RS as a promising therapeutic agent for ischemic brain injury, targeting SIRT1 to restore MB. Conclusion: RS mitigates neuronal apoptosis and mitochondrial dysfunction in CCI through SIRT1- dependent MB activation