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

Abstract

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 (<i>p</i> < 0.01). Esketamine co-treatment significantly alleviated these propofol-induced changes (<i>p</i> < 0.01). However, the neuroprotective effects of esketamine were diminished by pre-treatment with either LY294002 or the autophagy activator rapamycin (<i>p</i> < 0.01).<h4>Conclusion</h4>Esketamine ameliorates propofol-induced long-term cognitive impairments in juvenile rats by suppressing excessive autophagy through activation of the PI3K/Akt/mTOR signaling pathway.

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