Investigating the Mechanisms of Esketamine in Treating Propofol-Induced Cognitive Impairment in Elderly Rats.
Jieru Zhang, Guofeng Xu, Xiaoli Wang, Leyan Qiao
Discovery medicine April 1, 2025 DOI: 10.24976/Discov.Med.202537195.60 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Aged rats |
| Intervention | Esketamine |
| Topics | Esketamine |
| Keywords | Mtor-bdnf pathway Neuronal autophagy Postoperative cognitive dysfunction Propofol Anesthesia safety Cognitive protection Neuropharmacology Geriatric medicine Surgical medicine |
| Key findings | Esketamine reversed propofol-induced cognitive impairment in aged rats by inhibiting the mTOR-BDNF pathway and restoring neuronal autophagy. |
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.
Comparable studies
Other preclinical and animal studies on esketamine, most cited first.