Chikusetsu saponin IVa alleviated sevoflurane-induced neuroinflammation and cognitive impairment by blocking NLRP3/caspase-1 pathway

Abstract

Neuroinflammation plays a dominant role in the progression of postoperative cognitive dysfunction (POCD). This study was carried out to explore the neuroprotective effect of Chikusetsu saponin IVa (ChIV) against sevoflurane-induced neuroinflammation and cognitive impairment. The neuroprotective activity of ChIV against sevoflurane-induced cognitive dysfunction in aged rats was evaluated by Morris water maze, NOR test and Y-maze test, respectively. The expression of NLRP3, ASC and caspase-1, pro-inflammatory cytokines and apoptotic-related protein were detected in the hippocampus and primary neurons using western blot. TUNEL assay and immunohistochemistry staining were applied to assess the apoptotic cell and number of NLRP3-positive cells in the hippocampus. The oxiSelectIn Vitro ROS/RNS assay kit was used to detect the ROS level. The CCK-8 assay was applied to measure the viability of primary neurons. Flow cytometry was carried out to determine cell apoptosis. Pretreatment with ChIV significantly alleviated neurological dysfunction in aged rat exposure to sevoflurane. Mechanistically, ChIV treatment significantly alleviated sevoflurane-induced apoptotic cell and neuroinflammation. Of note, the neuroprotective effect of ChIV against sevoflurane-induced neurotoxicity through blocking NLRP3/caspase-1 pathway. In consistent with in vivo studies, ChIV was also able to repress sevoflurane-induced apoptosis and neuroinflammation in primary neurons. Furthermore, pretreatment with NLRP3/caspase-1 pathway inhibitor (MCC950) significantly augmented the neuroprotective effect of ChIV. Our finding confirmed that ChIV provides a neuroprotective effect against sevoflurane-induced neuroinflammation and cognitive impairment by blocking the NLRP3/caspase-1 pathway, which may be an effective strategy for the clinical treatment of elderly patients with POCD induced by anesthesia.