Effect of esketamine on cerebral ischemia-reperfusion injury and association with mitochondrial stress in mice
10.3760/cma.j.cn131073.20231024.00211
- VernacularTitle:艾司氯胺酮对小鼠脑缺血再灌注损伤的影响及其与线粒体应激的关系
- Author:
Xia WANG
1
;
Peilong LI
;
Yaru HUANG
;
Wenying CHI
;
Gongming WANG
;
Fanjun MENG
Author Information
1. 山东第一医科大学（山东省医学科学院）研究生部，济南 250117
- Keywords:
Esketamine;
Reperfusion injury;
Brain;
Mitochondria;
Stress, physiological
- From:
Chinese Journal of Anesthesiology
2024;44(2):176-181
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To evaluate the effect of esketamine on cerebral ischemia-reperfusion (I/R) injury and the association with mitochondrial stress in mice.Methods:The experiment was performed in two parts. Part Ⅰ Eighteen SPF male C57BL/6 mice, aged 8-12 weeks, with body mass index of 28-30 g, were divided into 3 groups ( n=6 each) by a random number table method: sham operation group (S group), cerebral I/R group (IR group), and esketamine plus cerebral I/R group (E+ IR group). Cerebral I/R was produced by occlusion of middle cerebral artery for 1 h followed by 24-h reperfusion in anesthetized mice.Esketamine 10 mg/kg was intraperitoneally injected at 20 min before developing the model in E group. Neurological function was evaluated using the Zea Longa score and balance beam test (Feeney score). The cerebral infarct size was determined by TTC staining. Part Ⅱ Primary cortical neurons were isolated and cultured and then divided into 3 groups ( n=42 each) using a random number table method: control group (group C), oxygen-glucose deprivation-reoxygenation (OGD/R) group, and esketamine plus OGD/R group (group E+ OGD/R). Cells were subjected to O 2-glucose deprivation for 1 h followed by restoration of O 2-glucose supply for 24 h. The cells were treated with 25 μmol/L esketamine for 40 min before preparing the model in E+ OGD/R group. The neuronal viability was measured by the CCK-8 assay. The ultrastructure of neurons was observed with a transmission electron microscope. The levels of reactive oxygen species (ROS), glutathione peroxidase (GSH-px) and malondialdehyde (MDA) were determined, and the mitochondrial membrane potential was determined by JC-1 kit. The neuronal apoptosis was detected by TUNEL staining, and the apoptosis rate of neurons was calculated. The expression of Bax, cytochrome C (CytC), cleaved-caspase-9, caspase-3 and cleaved-caspase-3 was detected by Western blot. Results:Part Ⅰ Compared with S group, the Zea Longa score, Feeney score and cerebral infarct size were significantly increased in IR group ( P<0.01). Compared with IR group, the Zea Longa score, Feeney score and cerebral infarct size were significantly decreased in E+ IR group ( P<0.01). Part Ⅱ Compared with C group, the cell viability and activity of GSH-px were significantly decreased, the apoptosis rate of neurons, levels of ROS and MDA, mitochondrial membrane potential, and cleaved-caspase-3/caspase-3 ratio were increased, and the expression of Bax, Cyt C and cleaved-caspase-9 was up-regulated in OGD/R group ( P<0.01). Compared with OGD/R group, the cell viability and activity of GSH-px were significantly increased, the apoptosis rate of neurons, levels of ROS and MDA, mitochondrial membrane potential, and cleaved-caspase-3/caspase-3 ratio were decreased, and the expression of Bax, Cyt C and cleaved-caspase-9 was down-regulated in E+ OGD/R group ( P<0.01). Conclusions:Esketamine can alleviate cerebral I/R injury in mice, and the mechanism may be related to inhibition of mitochondrial stress in neurons, improvement in mitochondrial function, and inhibition of mitochondria-dependent apoptosis in neurons.
