Salidroside nanoliposomes alleviate postoperative cognitive dysfunction by inhibiting Fos-mediated neuroinflammation

Postoperative cognitive dysfunction (POCD) is a complication that occurs mostly after cardiac, skeletal, and other surgical procedures, commonly present in the elderly. Salidroside (SAL) is an active ingredient extracted from the herb rhodiola rosea that has been verified to protect nerve function and inhibit neuroinflammatory responses. SAL nanoliposomes (SAL-Nanos) were first prepared, and the apparent morphology was observed by electron microscopy and transmission electron microscopy, followed by evaluation using zeta potential and encapsulation efficiency. POCD mouse models were established using exploratory laparotomy and then subjected to Morris water maze (MWM). Mouse hippocampal tissues were subjected to hematoxylin-eosin (H&E) staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and enzyme-linked immunosorbent assay (ELISA). Subsequently, mouse hippocampal tissues from each group were taken for transcriptome sequencing, namely differential analysis, trend analysis, and enrichment analysis. Neuroinflammation models were constructed using LPS-induced microglia to observe the effects of SAL and SAL-Nanos on inflammatory factor levels and Fos expression. Changes in inflammatory factor levels and Fos expression were observed by knocking down Fos expression in microglia. Administering Fos inhibitor (T5224), pathological phenotypic changes in POCD mice and Fos expression levels in hippocampal tissues were observed by H&E staining, TUNEL staining, and ELISA. SAL-Nanos were successfully prepared and could well ameliorate hippocampal inflammation, reduce apoptosis, and protect memory in POCD mice. Transcriptome analysis identified the Toll-like receptor (TLR) signaling pathway and its related molecule Fos to be associated with the improvement of POCD mice by SAL-Nanos. Subsequent studies found that SAL-Nanos can significantly suppress the level of LPS-induced microglia inflammation, improve cell viability, and reduce Fos expression. In addition, Fos knockdown could effectively suppress LPS-induced inflammatory factor levels. It was further demonstrated by in vivo assays that inhibition of Fos expression can significantly alleviate the inflammation level in hippocampal tissues of POCD mice, inhibit apoptosis, and improve memory. SAL-Nanos exhibit a more significant therapeutic effect on POCD mice compared to SAL, and its relief effect on POCD mice may inhibit neuroinflammation by down-regulating Fos expression.