• Yanan Li, Xinran Li, Jinghua Zhao, Lina Li, Yuxin Wang, Yiming Zhang, Yu Chen, Wenhan Liu, and Li Gao.
• College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
• Neuroscience. 2018 Sep 15; 388: 460-471.

AbstractEvery year between 0.75% and 2% of pregnant women require surgery that is related to either the pregnancy or other medical problems in USA. Therefore, the neurodegeneration following anesthesia in a variety of animal models has attracted our attention. Neurotoxic effects of ketamine cannot be ignored. In contrast, some anesthetics, including midazolam, protect neurons and increase dendritic spine density. However, the mechanism of neuroprotection by midazolam is not clear, and whether midazolam can relieve the damage caused by ketamine is unknown. Therefore, in this study, we explored the effects of midazolam on ketamine anesthesia. We measured protein levels of cleaved-caspase-3 (c-caspase-3), beclin-1, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), autophagy-related gene 4 (ATG4), ATG5, p62 (SQSTM1), and the autophagy marker light chain 3 (LC3) in hippocampus by Western analysis. We also measured total antioxidant capacity (T-AOC), and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in hippocampus and PC12 cells. Results showed that ketamine induced apoptosis through activation of the mitochondrial pathway by increasing the expression of c-caspase-3 and Bax, and decreasing the expression of Bcl-2 at the protein level. Ketamine also increased the expression of LC3II and ATG5, proteins, decreased the expression of ATG4 and P62, and finally induced autophagy. Ketamine promoted the production of ROS and MDA, and reduced total antioxidant capacity (T-AOC); these effects were attenuated by midazolam. In conclusion, ketamine induces toxicity in human neurons through ROS-mediated activation of mitochondrial apoptotic pathway and autophagy. The harmful effects of ketamine can be ameliorated by midazolam.Copyright © 2018. Published by Elsevier Ltd.

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