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Integr. Neurosci."],"abstract":"<jats:p>Background: 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. Methods: 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. Results: 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 &lt; 0.01). Esketamine co-treatment significantly alleviated these propofol-induced changes (p &lt; 0.01). However, the neuroprotective effects of esketamine were diminished by pre-treatment with either LY294002 or the autophagy activator rapamycin (p &lt; 0.01). Conclusion: Esketamine ameliorates propofol-induced long-term cognitive impairments in juvenile rats by suppressing excessive autophagy through activation of the PI3K\/Akt\/mTOR signaling pathway.<\/jats:p>","DOI":"10.31083\/jin50741","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:16:31Z","timestamp":1790698591000},"source":"Crossref","is-referenced-by-count":0,"title":["Esketamine Ameliorates Propofol-Induced Long-Term Cognitive Impairments in Juvenile Rats by Suppressing Autophagy via Activating the PI3K\/Akt\/mTOR Signaling Pathway"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5338-6950","authenticated-orcid":true,"given":"Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5702-4285","authenticated-orcid":true,"given":"Yin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5556-4549","authenticated-orcid":true,"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-6561","authenticated-orcid":true,"given":"Xuexue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0196-4544","authenticated-orcid":true,"given":"Na","family":"Qi","sequence":"additional","affiliation":[{"name":"Graduate School of Xinjiang Medical University, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6254-3152","authenticated-orcid":true,"given":"Xueying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1645-4918","authenticated-orcid":true,"given":"Guiping","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, People\u2019s Hospital of Xinjiang Uygur Autonomous Region; Xinjiang Clinical Research Center for Anesthesia Management, 830000 Urumqi, Xinjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Wong-Kee-You AMB, Loveridge-Easther C, Mueller C, Simon N, Good WV. 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