Esketamine Ameliorates Propofol-Induced Long-Term Cognitive Impairments in Juvenile Rats by Suppressing Autophagy via Activating the PI3K/Akt/mTOR Signaling Pathway.
Yang Wang, Yin Li, Zhe Chen, Xuexue Zhang, Na Qi, Xueying Chen, Guiping Xu
Journal of Integrative Neuroscience September 21, 2026 DOI: 10.31083/jin50741 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled animal experiment Peer reviewed |
|---|---|
| Sample size | 72 |
| Population | Juvenile Sprague-Dawley rats of both sexes at postnatal day 7 |
| Interventions | Propofol Esketamine LY294002 Rapamycin |
| Duration | Treatments administered daily for five consecutive days |
| Measures | Y-maze test, Morris water maze test, Western blotting, immunofluorescence, histopathological staining, transmission electron microscopy |
| Topics | Esketamine |
| Keywords | Autophagy Phosphatidylinositol 3-kinase Propofol Protein kinase b Rats |
| Key findings | Propofol exposure in juvenile rats produced learning and memory impairments, hippocampal neuronal damage, suppressed PI3K/Akt/mTOR signaling, excessive autophagy, and elevated pro-inflammatory cytokines. Esketamine co-treatment significantly alleviated these changes, and its protection was diminished by the PI3K inhibitor LY294002 or the autophagy activator rapamycin, supporting the authors' proposal that esketamine acts by activating PI3K/Akt/mTOR and suppressing excessive autophagy. |
Abstract
Repeated propofol exposure during neurodevelopment induces long-term cognitive deficits in rats, potentially through dysregulated hippocampal neuronal autophagy and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Esketamine has been reported to exert neuroprotective effects; however, the underlying mechanism remains unclear. In the present study, we investigated whether esketamine could ameliorate propofol-induced long-term memory and learning impairments in juvenile rats by suppressing autophagy via activation of the PI3K/Akt/mTOR pathway. Seventy-two Sprague-Dawley rats of both sexes at postnatal day 7 were randomly assigned to one of six groups: Control, Propofol, Esketamine + Propofol, LY294002 (PI3K inhibitor) + Esketamine + Propofol, Rapamycin + Propofol, and Rapamycin + Esketamine + Propofol. All treatments were administered daily for five consecutive days. Cognitive performance was assessed using both the Y-maze test and the Morris water maze test. Hippocampal neuronal pathology was evaluated by histopathological staining and transmission electron microscopy. The concentrations of pro-inflammatory cytokines and expression levels of proteins related to the PI3K/Akt/mTOR pathway and autophagy were measured using Western blotting and immunofluorescence. Rats exposed to propofol showed significant learning and memory impairments, hippocampal neuronal damage, suppression of the PI3K/Akt/mTOR pathway, excessive autophagy, and elevated levels of pro-inflammatory cytokines (p < 0.01). Esketamine co-treatment significantly alleviated these propofol-induced changes (p < 0.01). However, the neuroprotective effects of esketamine were diminished by pre-treatment with either LY294002 or the autophagy activator rapamycin (p < 0.01). Esketamine ameliorates propofol-induced long-term cognitive impairments in juvenile rats by suppressing excessive autophagy through activation of the PI3K/Akt/mTOR signaling pathway.
Comparable studies
Other preclinical and animal studies on esketamine, most cited first.
Citations in the library
Cites 4
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- Investigating the Mechanisms of Esketamine in Treating Propofol-Induced Cognitive Impairment in Elderly Rats. Discovery medicine April 1, 2025
- Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice. British Journal of Anaesthesia December 1, 2023
- Esketamine alleviates postoperative depression-like behavior through anti-inflammatory actions in mouse prefrontal cortex. Journal of Affective Disorders April 1, 2022