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

Esketamine improved cognitive impairment caused by the anesthetic propofol in aged rats. Propofol worsened performance on the water maze and sugar-water preference tests, increased neuronal damage and beta-amyloid deposits, and raised markers of inflammation and apoptosis while reducing autophagy-related proteins and synaptic proteins. Esketamine reversed these effects, including restoring levels of BDNF and ATG-5, and decreasing p-Tau and caspase-3. The findings suggest that esketamine acts by inhibiting the mTOR-BDNF pathway, thereby lifting the suppression of neuronal autophagy and protecting against propofol-induced cognitive dysfunction.

Study at a glance

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.