Exploring Sevoflurane promotes hippocampal neuron mitophagy in elderly postoperative cognitive dysfunction by...

As a common anesthetic, Sevoflurane may be involved in the development of postoperative cognitive dysfunction (POCD) in the elderly. This study aims to investigate whether Sevoflurane regulates mitophagy in hippocampal neurons in elderly POCD through HSP90AA1, using a network pharmacology-based approach. Multiple databases were used to screen the common targets of Sevoflurane, mitophagy and elderly POCD, and GO and KEGG pathway enrichment analyses were performed. The protein-protein interaction network was constructed using STRING database and Cytoscape software, and the binding characteristics of Sevoflurane to the core target HSP90AA1 were verified by molecular docking and dynamics simulation. For cellular experiments, mouse hippocampal neuronal cells (HT22) were treated with Sevoflurane, and rescue experiments were performed by knocking down HSP90AA1 (sh-HSP90AA1). Cell viability, oxidative stress, mitochondrial membrane potential (MMP), the expression of mitophagy markers and cell apoptosis were evaluated by CCK8 assay, LDH release detection, ROS detection, JC-1 staining, western blot and flow cytometry. A total of 42 common targets of Sevoflurane, mitophagy and elderly POCD were screened, among which HSP90AA1 was identified as one of the key hub targets. Molecular docking showed that Sevoflurane had a stable binding ability with HSP90AA1. Cell experiments showed that Sevoflurane treatment significantly inhibited HT22 cell viability and p63 protein expression, while increased LDH release, ROS level, MMP depolarization, LC3-II/LC3-I, PINK1, Parkin, HSP90AA1 protein expression, and cell apoptosis. However, knockdown of HSP90AA1 reversed the above cell injury effects induced by Sevoflurane. Sevoflurane may promote oxidative stress, mitophagy and apoptosis of hippocampal neurons by upregulating HSP90AA1, thereby aggravating the process of POCD in the elderly. These results suggest that HSP90AA1 is a potential key target for Sevoflurane-mediated neuronal injury.