Department of Psychiatry and Behavioural Neuroscience, Faculty of Health Science, McMaster University, Hamilton, ON, Canada.
Department of Psychiatry and Behavioural Neuroscience, Faculty of Health Science, McMaster University, Hamilton, ON, Canada.
Neurotoxicology. 2022 Jul;91:321-328. doi: 10.1016/j.neuro.2022.06.004. Epub 2022 Jun 18.
Ketamine has traditionally been used as a dissociative anesthetic agent and more recently as a treatment for treatment-resistant depression. However, there is growing concern over the increased use of ketamine in recreational and therapeutic settings due to the potential neurotoxic effects. Recent studies have demonstrated that ketamine is cytotoxic in several cell types, such as fibroblasts, hepatocytes, uroepithelial cells, and adult induced pluripotent stem cells (iPSCs). Ketamine has been shown to dysregulate calcium signalling, increase reactive oxygen species (ROS) production, and impair mitochondrial function, ultimately leading to apoptosis. However, it is unclear whether endoplasmic reticulum (ER) stress plays a role in ketamine associated neurotoxicity in striatal neurons. Disruption to ER homeostasis can initiate ER-mediated cell death, which has been implicated in several neurodegenerative diseases. Thus, the purpose of this study was to determine whether ketamine's neurotoxic effects involve an ER stress-dependent pathway and to elucidate the underlying mechanisms involved in its neurotoxic effects. Mouse striatal cells were treated with various concentrations of ketamine (10 μM, 100 μM, 1 mM) or DMEM for 9-72 hrs. Cell viability was assessed using the MTT assay, and changes in gene expression of ER stress markers were evaluated using RT-qPCR. MTT results revealed that 1 mM ketamine decreased cell viability in striatal cells after 24 h of treatment. Gene expression studies complemented these findings such that ketamine upregulated pro-apoptotic ER stress markers, including X-box binding protein 1 (XBP1), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) and downregulated pro-survival ER stress proteins such as GRP78, MANF and CDNF. Ketamine activated all three stress sensing pathways including PERK, IRE1, and ATF6. Taken together, our results show that ketamine-induced neurotoxicity is mediated through an ER stress-dependent apoptotic pathway.
氯胺酮传统上被用作分离麻醉剂，最近也被用作治疗难治性抑郁症的药物。然而，由于其潜在的神经毒性作用，氯胺酮在娱乐和治疗环境中的使用增加引起了人们的关注。最近的研究表明，氯胺酮在几种细胞类型中具有细胞毒性，如成纤维细胞、肝细胞、尿上皮细胞和成人诱导多能干细胞（iPSC）。氯胺酮已被证明能使钙信号失调、增加活性氧（ROS）的产生、损害线粒体功能，最终导致细胞凋亡。然而，目前尚不清楚内质网（ER）应激是否在纹状体神经元的氯胺酮相关神经毒性中起作用。ER 平衡的破坏会引发 ER 介导的细胞死亡，这与几种神经退行性疾病有关。因此，本研究的目的是确定氯胺酮的神经毒性作用是否涉及 ER 应激依赖性途径，并阐明其神经毒性作用的潜在机制。用不同浓度的氯胺酮（10 μM、100 μM、1 mM）或 DMEM 处理小鼠纹状体细胞 9-72 小时。用 MTT 测定法评估细胞活力，并用 RT-qPCR 评估 ER 应激标志物的基因表达变化。MTT 结果表明，1 mM 氯胺酮在处理 24 小时后降低了纹状体细胞的活力。基因表达研究补充了这些发现，表明氯胺酮上调了促凋亡的 ER 应激标志物，包括 X 盒结合蛋白 1（XBP1）、激活转录因子 4（ATF4）和 C/EBP 同源蛋白（CHOP），并下调了促存活的 ER 应激蛋白，如 GRP78、MANF 和 CDNF。氯胺酮激活了所有三条应激感应途径，包括 PERK、IRE1 和 ATF6。总之，我们的结果表明，氯胺酮诱导的神经毒性是通过 ER 应激依赖性凋亡途径介导的。
