Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei College of Arts and Science, Xiangyang 441021, Hubei, People's Republic of China.
Drug Des Devel Ther. 2020 Nov 9;14:4789-4800. doi: 10.2147/DDDT.S256319. eCollection 2020.
Widely used in anesthesia, ketamine is reported to induce neurotoxicity in patients. This study aimed to investigate the molecular regulatory mechanism of long non-coding RNA (lncRNA) KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in ameliorating ketamine-induced neural injury.
Sprague-Dawley rats were intraperitoneally injected with ketamine to induce neuronal injury. PC-12 cells treated with ketamine were used as the cell model. Ketamine-induced aberrant expression of KCNQ1OT1, miR-206 and brain-derived neurotrophic factor (BDNF) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of KCNQ1OT1 and miR-206 on ketamine-induced neural injury in PC-12 cells were then examined by MTT and LDH assay. The regulatory relationships between KCNQ1OT1 and miR-206, and miR-206 and BDNF were detected by dual-luciferase reporter assay.
Ketamine induced the apoptosis of neurons of the hippocampus in rats, and the apoptosis of PC-12 cells, accompanied by down-regulation of KCNQ1OT1 and BDNF expressions, and up-regulation of miR-206 expression. Overexpression of KCNQ1OT1 enhanced the resistance to apoptosis of PC-12 cells and significantly ameliorated ketamine-induced nerve injury, while transfection of miR-206 had opposite effects. Mechanistically, KCNQ1OT1 could target miR-206 and reduce its expression level, in turn indirectly increase the expression level of BDNF, and play a protective role in neural injury.
KCNQ1OT1/miR-206/BDNF axis is demonstrated to be an important regulatory mechanism in regulating ketamine-induced neural injury. Our study helps to clarify the mechanism by which ketamine exerts its toxicological effects and provides clues for the neuroprotection during anesthesia.
氯胺酮在麻醉中广泛应用，但有报道称其可诱导患者发生神经毒性。本研究旨在探讨长链非编码 RNA（lncRNA）KCNQ1 反义链/反义转录本 1（KCNQ1OT1）在改善氯胺酮诱导的神经损伤中的分子调控机制。
腹腔注射氯胺酮诱导大鼠神经元损伤，建立细胞模型。采用实时定量聚合酶链反应（qRT-PCR）检测氯胺酮诱导的 KCNQ1OT1、miR-206 和脑源性神经营养因子（BDNF）的异常表达。通过 MTT 和 LDH 检测 KCNQ1OT1 和 miR-206 对 PC-12 细胞氯胺酮诱导神经损伤的影响。双荧光素酶报告基因检测 KCNQ1OT1 与 miR-206、miR-206 与 BDNF 的调控关系。
氯胺酮诱导大鼠海马神经元凋亡，PC-12 细胞凋亡，同时 KCNQ1OT1 和 BDNF 表达下调，miR-206 表达上调。过表达 KCNQ1OT1 增强了 PC-12 细胞的抗凋亡能力，显著改善了氯胺酮诱导的神经损伤，而转染 miR-206 则产生相反的效果。机制上，KCNQ1OT1 可以靶向 miR-206 并降低其表达水平，进而间接增加 BDNF 的表达水平，在神经损伤中发挥保护作用。
KCNQ1OT1/miR-206/BDNF 轴被证明是调节氯胺酮诱导的神经损伤的重要调控机制。本研究有助于阐明氯胺酮发挥毒性作用的机制，并为麻醉期间的神经保护提供线索。
