Role of Esketamine in Attenuating Neuroinflammation and Improving Postoperative Cognitive Function via Autophagy Activation Through PARP1 Targeting

Dec 2, 2025Physiological research

Esketamine may reduce brain inflammation and improve thinking after surgery by boosting cell cleanup through PARP1

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Abstract

Exploratory laparotomy induced postoperative cognitive dysfunction (POCD) and neuroinflammation in mice.

Treatment with esketamine may alleviate POCD by inhibiting the expression of PARP1.
Esketamine could increase levels of SIRT1, which is associated with promoting cellular autophagy.
Reduction in neuroinflammation was observed following esketamine treatment, suggesting its potential role in managing POCD.
The regulation of the PARP1-SIRT1 pathway by esketamine is linked to improved cognitive outcomes in the tested model.

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Postoperative cognitive dysfunction (POCD) substantially influences patient outcomes, with its pathophysiology potentially linked to neuroinflammation induced by surgical procedures and anesthesia. Previous research has indicated that esketamine may alleviate neuroinflammation. Therefore, elucidating the mechanisms through which esketamine modulates neuroinflammation to ameliorating POCD is crucial for advancing its clinical management. An in vivo model of POCD was established using C57BL/6J mice subjected to exploratory laparotomy. Cognitive performance was evaluated through the Morris water maze. Subsequently, hippocampal tissue samples were collected to measure changes in the levels of IL-1beta, IL-6, TNF-alpha, PARP1, SIRT1, LC3, and P62. In vitro experiments were performed using BV2 microglial cells treated with lipopolysaccharides (LPS) to induce inflammation and a PARP1 plasmid to create PARP1 overexpression (OvPARP1) models. These models were treated with esketamine, followed by assessment of changes in the previously mentioned indicators. Immunofluorescence microscopy was used to examine PARP1 expression, while transmission electron microscopy was used to analyze cellular autophagy. Exploratory laparotomy induced POCD and triggered neuroinflammation within the hippocampus of the mice. Treatment with esketamine alleviated POCD by inhibiting OvPARP1 expression and increasing SIRT1 levels, which promoted cellular autophagy and reduced neuroinflammation. Esketamine regulates the PARP1-SIRT1 pathway, thereby activating autophagy, reducing neuro-inflammation, and improving POCD. These findings provide novel insights into potential therapeutic strategies for the management of POCD. Key words Autophagy " Esketamine " Neuroinflammation " PARP1 " Postoperative cognitive dysfunction.

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Role of Esketamine in Attenuating Neuroinflammation and Improving Postoperative Cognitive Function via Autophagy Activation Through PARP1 Targeting

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