Underlying Mechanisms of Memory Deficits Induced by Etomidate Anesthesia in Aged Rat Model

Abstract

Background:Etomidate (R-1-[1-ethylphenyl] imidazole-5-ethyl ester) is a widely used anesthetic drug that had been reported to contribute to cognitive deficits after general surgery. However, its underlying mechanisms have not been fully elucidated. In this study, we aimed to explore the neurobiological mechanisms of cognitive impairments that caused by etomidate.Methods:A total of 30 Sprague-Dawley rats were used and divided into two groups randomly to receive a single injection of etomidate or vehicle. Then, the rats’ spatial memory ability and neuronal survival were evaluated using the Morris water maze test and Nissl staining, respectively. Furthermore, we analyzed levels of oxidative stress, as well as cyclic adenosine 3’,5’-monophosphate response element-binding (CREB) protein phosphorylation and immediate early gene (IEG, including Arc, c-fos, and Egr1) expression levels using Western blot analysis.Results:Compared with vehicle-treated rats, the etomidate-treated rats displayed impaired spatial learning (day 4: 27.26 ± 5.33 s vs. 35.52 ± 3.88 s, t = 2.988, P = 0.0068; day 5: 15.84 ± 4.02 s vs. 30.67 ± 4.23 s, t = 3.013, P = 0.0057; day 6: 9.47 ± 2.35 s vs. 25.66 ± 4.16 s, t = 3.567, P = 0.0036) and memory ability (crossing times: 4.40 ± 1.18 vs. 2.06 ± 0.80, t = 2.896, P = 0.0072; duration: 34.00 ± 4.24 s vs. 18.07 ± 4.79 s, t = 3.023, P = 0.0053; total swimming distance: 40.73 ± 3.45 cm vs. 27.40 ± 6.56 cm, t = 2.798, P = 0.0086) but no neuronal death. Furthermore, etomidate did not cause oxidative stress or deficits in CREB phosphorylation. The levels of multiple IEGs (Arc: vehicle treated rats 100%, etomidate treated rats 86%, t = 2.876, P = 0.0086; c-fos: Vehicle treated rats 100%, etomidate treated rats 72%, t = 2.996, P = 0.0076; Egr1: Vehicle treated rats 100%, etomidate treated rats 58%, t = 3.011, P = 0.0057) were significantly reduced in hippocampi of etomidate-treated rats.Conclusion:Our data suggested that etomidate might induce memory impairment in rats via inhibition of IEG expression.

Oxidative stress under general intravenous and inhalation anaesthesia

“…Similar was observed in animal studies. It does not seem to affect MDA levels or change SOD activity ( 57 ) in rat brain, while it significantly decreased MDA and increased GSH levels in the spinal cord after injury ( 58 ).…”

“…In adult male rats it also increased MDA in the lungs, but decreased it in the kidney and brain ( 67 ). It also significantly reduced liver MDA levels in rats with ischaemia/reperfusion injury ( 57 ). Compared to isoflurane in another study ( 68 ), it produced significantly lower TBARS levels.…”

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System

“…For instance, Chastain-Potts et al showed that sevoflurane exposure induces upregulation of Arc and Jun-B mRNA expression in the subiculum, which is crucial for synaptic plasticity and normal neuronal development [ 11 ]. Etomidate reduces the protein expression levels of memory-associated IEG in the rat hippocampus, including Arc, c-fos, and Egr1 [ 13 ]. However, there is some evidence that reveals distinct expression patterns in IEG under the same stimuli.…”

Effect of dexmedetomidine combined with etomidate on IL‑17A and S‑100β expression levels in rats with postoperative cognitive dysfunction

“…It has been shown (16) that dexmedetomidine could improve the neuronal apoptosis caused by isoflurane in neonatal rats. In addition, Etomidate is a type of drug used for general anesthesia and sedation (17), which has the advantages of quick effect, short acting time and little effect on circulation.…”