Bupivacaine exacerbates postoperative cognitive dysfunction by suppressing YES1-mediated YAP1 phosphorylation

Bupivacaine is a commonly used local anesthetic in both human and equine medicine. This study aimed to explore the molecular mechanism of bupivacaine-induced postoperative cognitive dysfunction (POCD). Bioinformatics analysis identified YES proto-oncogene 1 (YES1) as a key player. A POCD mouse model was developed using bupivacaine and surgery, followed by assessment of cognitive function and DNA damage. SH-SY5Y cells were exposed to bupivacaine, and DNA damage was analyzed. Verteporfin, a Yes-associated protein 1 (YAP1) inhibitor, was used in both mice and cells to study its effects. Bupivacaine increased escape latency and decreased the number of platform crossings in the Morris water maze test, and reduced total distance traveled in the open field test and discrimination index in the novel object recognition test, which was associated with the suppression of YES1 expression in the hippocampal tissue of mice. YES1 overexpression alleviated POCD and neuronal DNA damage induced by bupivacaine in mice by promoting YAP1 phosphorylation. Treatment with verteporfin reversed the alleviating effects of YES1 overexpression on neuronal DNA damage and exacerbated POCD in mice. In conclusion, bupivacaine induces POCD by suppressing YES1 expression and YAP1 phosphorylation, leading to DNA damage.