As a widely used general anesthetic, sevoflurane has been found to induce cognitive and memory defectsin the elderly. This may increase the risk of Alzheimer’s disease. This study explores the neuroprotective effect of hispidulin, a natural flavone compound, against sevoflurane-induced memory dysfunction.

The effect of sevoflurane exposure on memory function was evaluated by novel object recognition and Y-maze testing using an aged rat model. The apoptotic cell death in the hippocampus of rats was assessed using a TUNEL assay. The levels of protein markers for cell apoptosis in the hippocampus were examined by western blot. The effect of sevoflurane and hispidulin on the accumulation of Aβ was also examined. In addition, the attenuating effect of hispidulin on sevoflurane-induced neuroinflammation was assessed by measuring the expression of pro-inflammatory cytokines and the translocation of NF-κB p65 from cytosol to nucleus. The activation of Nrf2 in the hippocampus was also detected. Moreover, the effect of hispidulin on sevoflurane-induced apoptosis, Aβ accumulation, and neuroinflammation was also examined in human neuroglioma H4 cells, which served as an in vitro model.To further examine the role of Nrf2 in the neuroprotective activity of hispidulin against sevoflurane-neurotoxicity, H4 cells were transfected with Nrf2 targeting siRNA, which led to a significant reduction in Nrf2 expression.

Both novel object recognition and Y-maze testing showed that sevoflurane significantly impaired the memory of aged rats, which was significantly reversed by pretreatment with hispidulin. Mechanistically, our findings revealed that hispidulin significantly attenuated sevoflurane-induced apoptotic cell death, Aβ accumulation, and neuroinflammation. In agreement with in vivo studies, hispidulin was also able to attenuate sevoflurane-induced apoptosis, increases of Aβ levels, and neuroinflammation in H4 cells. Moreover, our results showed that Nrf2 activation mediated the neuroprotective effect of hispidulin against sevoflurane-induced neurotoxicity by demonstrating that knockdown of Nrf2 in H4 cells significantly compromised its protective effects.

As our study provides in vitro and in vivo evidence that hispidulin can offer protection against sevoflurane-induced neurological dysfunction, hispidulin has the potential to be a neuroprotective agent that can improve the cognitive and memory function of elderly patients undergoing anesthesia.