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Bupivacaine exacerbates postoperative cognitive dysfunction by suppressing YES1-mediated YAP1 phosphorylation
1Department of Anesthesiology, Huai'an Hospital of Traditional Chinese Medicine, No. 3, Heping Road, Qingjiangpu District, Huai'an, 223001, Jiangsu, People's Republic of China.
Experimental Brain Research
|October 28, 2025
Summary
Bupivacaine causes postoperative cognitive dysfunction (POCD) by reducing YES proto-oncogene 1 (YES1) and YAP1 phosphorylation, leading to DNA damage. Restoring YES1 may reverse these effects, offering potential therapeutic targets for POCD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Bupivacaine is a widely used local anesthetic in human and equine medicine.
- Postoperative cognitive dysfunction (POCD) is a concerning complication following anesthesia and surgery.
- The precise molecular mechanisms underlying bupivacaine-induced POCD remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanism of bupivacaine-induced postoperative cognitive dysfunction (POCD).
- To investigate the role of YES proto-oncogene 1 (YES1) and Yes-associated protein 1 (YAP1) signaling in bupivacaine-induced POCD.
- To evaluate the therapeutic potential of targeting YES1/YAP1 signaling.
Main Methods:
- Development of a POCD mouse model using bupivacaine and surgery.
- Assessment of cognitive function using behavioral tests (Morris water maze, open field test, novel object recognition).
- Analysis of neuronal DNA damage and molecular signaling pathways (YES1, YAP1 phosphorylation) in both in vivo and in vitro models (SH-SY5Y cells).
- Pharmacological intervention using verteporfin, a YAP1 inhibitor.
Main Results:
- Bupivacaine administration impaired cognitive functions in mice, evidenced by increased escape latency, reduced platform crossings, decreased locomotion, and lower discrimination index.
- These cognitive deficits were associated with suppressed YES1 expression and reduced YAP1 phosphorylation in hippocampal tissues.
- YES1 overexpression ameliorated bupivacaine-induced POCD and neuronal DNA damage by enhancing YAP1 phosphorylation.
- Verteporfin treatment reversed the protective effects of YES1 overexpression and worsened POCD and DNA damage.
Conclusions:
- Bupivacaine induces POCD by suppressing YES1 expression and subsequent YAP1 phosphorylation, leading to neuronal DNA damage.
- Targeting the YES1/YAP1 pathway represents a promising therapeutic strategy for mitigating bupivacaine-induced cognitive impairment.
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