Investigating the Mechanisms of Esketamine in Treating Propofol-Induced Cognitive Impairment in Elderly Rats.

Summary

A promising breakthrough shows that esketamine may protect elderly patients from cognitive decline caused by the common anesthetic propofol. The drug works by regulating brain cell maintenance through the mTOR-BDNF pathway, helping preserve memory and thinking abilities. Tests in older rats demonstrated improved learning, better mood, and healthier brain cells after esketamine treatment, suggesting a new way to prevent postoperative cognitive dysfunction in elderly patients.

Abstract

Common cognitive impairment in the elderly may be aggravated by the anesthetic propofol, whereas the mammalian target of rapamycin protein (mTOR)-brain-derived neurotrophic factor (BDNF) pathway and autophagy regulation play a key role in neuroprotection. In this study, we investigated whether esketamine can improve propofol-induced cognitive impairment in aged rats by affecting these mechanisms and revealed potential new therapeutic strategies. A propofol-induced age-related cognitive dysfunction model was used in the experiments. Behaviours were evaluated by the sugar-water preference test and the water maze, neuronal damage by Nissl staining, and neuronal apoptosis was detected by flow cytometry. Neuronal autophagy-related proteins phospho-mammalian target of rapamycin (p-mTOR), mTOR, BDNF, phospho-Unc-51 like autophagy activating kinase 1 (p-ULK1), Unc-51 like autophagy activating kinase 1 (ULK1), autophagy related 5 (ATG-5), and microtubule-associated protein 1 light chain 3-I/microtubule-associated protein 1 light chain 3-II (LC3-II/LC3-Ⅰ) were detected by western blotting (WB); immunohistochemistry was used to detect the deposition of β-amyloid (amyloid-beta, Aβ) in the hippocampal region and the positivity rate of caspase-3; postsynaptic density protein 95 (PSD95) and synapsin I (SYN1) levels were detected by WB. Water maze and sugar-water preference tests showed that the propofol group had longer escape latency, more platform crossings, lower platform quadrant time ratio, and reduced sugar-water preference, all improved by esketamine (p < 0.05). Nissl staining and immunohistochemistry revealed sparser neurons, darker staining, wrinkled morphology, and increased Aβ in the propofol group, all improved by esketamine (p < 0.05). WB showed increased phosphorylated Tau (p-Tau) and Aβ, higher apoptosis and caspase-3 positivity, and decreased BDNF, and ATG-5 in the propofol group, all reversed by esketamine. Propofol increased inflammatory markers and decreased SYN1, PSD95, and SYN expression, all of which were improved by esketamine (p < 0.05). By inhibiting the mTOR-BDNF pathway with esketamine, the inhibition of neuronal autophagy ultimately improves the cognitive dysfunction induced by propofol.

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