Esketamine Ameliorates Propofol-Induced Long-Term Cognitive Impairments in Juvenile Rats by Suppressing Autophagy via Activating the PI3K/Akt/mTOR Signaling Pathway

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 < 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). 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.