Underlying Mechanisms of Memory Deficits Induced by Etomidate Anesthesia in Aged Rat Model: Critical Role of Immediate Early Genes

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.