College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
Neuroscience. 2018 Sep 15;388:460-471. doi: 10.1016/j.neuroscience.2018.03.040. Epub 2018 Apr 7.
Every 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.
每年，美国有 0.75%至 2%的孕妇需要接受与妊娠或其他医疗问题相关的手术。因此，各种动物模型中的麻醉后神经退行性变引起了我们的注意。氯胺酮的神经毒性作用不容忽视。相比之下，一些麻醉剂，包括咪达唑仑，可以保护神经元并增加树突棘密度。然而，咪达唑仑的神经保护机制尚不清楚，咪达唑仑是否能缓解氯胺酮造成的损伤也尚不清楚。因此，在这项研究中，我们探讨了咪达唑仑对氯胺酮麻醉的影响。我们通过 Western 分析测量了海马体中裂解型半胱天冬酶-3（c-caspase-3）、beclin-1、B 细胞淋巴瘤-2（Bcl-2）、Bcl-2 相关 X 蛋白（Bax）、自噬相关基因 4（ATG4）、ATG5、p62（SQSTM1）和自噬标记物微管相关蛋白轻链 3（LC3）的蛋白水平。我们还测量了海马体和 PC12 细胞中的总抗氧化能力（T-AOC）、活性氧（ROS）和丙二醛（MDA）水平。结果表明，氯胺酮通过增加 c-caspase-3 和 Bax 的表达，降低 Bcl-2 的表达，从而通过激活线粒体途径诱导细胞凋亡。氯胺酮还增加了 LC3II 和 ATG5 蛋白的表达，降低了 ATG4 和 P62 的表达，最终诱导了自噬。氯胺酮促进了 ROS 和 MDA 的产生，降低了总抗氧化能力（T-AOC）；这些作用被咪达唑仑减弱。总之，氯胺酮通过 ROS 介导的线粒体凋亡途径和自噬激活诱导人神经元毒性。咪达唑仑可以减轻氯胺酮的有害作用。
