Department of Anaesthesiology, Ningxia Medical University, Yinchuan, NingXia, China.
Department of Anaesthesiology, General Hospital of Ningxia Medical University, Shengli Street, Yinchuan, 750004, NingXia, China.
J Mol Neurosci. 2019 May;68(1):58-65. doi: 10.1007/s12031-019-01282-3. Epub 2019 Mar 7.
Prolonged or repeated exposure to ketamine, a common anesthetic in pediatrics, has been shown to induce neurotoxicity and long-term neurocognitive deficits in the developing brain. Therefore, identification of potential therapeutic targets for preventing or alleviating such neurodegeneration and neuroapoptosis induced by ketamine is urgently needed. Remote ischemic preconditioning of the limb provides neuroprotection in different models of cerebral injury. Thus, the present study aimed to assess whether remote ischemic preconditioning could have a neuroprotective effect against neurotoxicity induced by ketamine. In our study, 96 newborn rats were assigned to one of four groups, including control, remote ischemic preconditioning, ketamine, and remote ischemic preconditioning plus ketamine. Ketamine was administered intraperitoneally in six doses of 20 mg/kg at 2-h intervals. Limb remote ischemic preconditioning comprised four ischemia (5 min)/reperfusion (5 min) cycles in the right hind limb using an elastic rubber band tourniquet. Histopathological characteristics of cerebral damage were assessed by H&E staining and transmission electron microscopy. TUNEL assay, immunohistochemical staining and immunoblot were employed to evaluate neural cell apoptosis. Learning and memory were evaluated using the Morris water maze. The results showed increased cleaved caspase-3 protein levels in the cerebral cortex and the hippocampal CA1 region, severe cell damage and DNA breakage, and decreased spatial learning and memory abilities in the ketamine group in comparison with controls. Notably, these changes were significantly reduced by remote ischemic preconditioning. These findings suggest that remote ischemic preconditioning ameliorates neuroapoptosis and neurocognitive impairment after repeated ketamine exposure in newborn rats.
反复或长期接触小儿科常用麻醉剂氯胺酮会导致发育中大脑的神经毒性和长期神经认知缺陷。因此，迫切需要确定潜在的治疗靶点，以预防或减轻氯胺酮引起的神经变性和神经细胞凋亡。肢体的远程缺血预处理在不同的脑损伤模型中提供神经保护。因此，本研究旨在评估远程缺血预处理是否对氯胺酮诱导的神经毒性具有神经保护作用。在我们的研究中，将 96 只新生大鼠分为四组，包括对照组、远程缺血预处理组、氯胺酮组和远程缺血预处理加氯胺酮组。氯胺酮通过腹腔内注射以 2 小时间隔给予 6 次 20mg/kg 的剂量。肢体远程缺血预处理包括在右侧后肢使用弹性橡胶带止血带进行 4 次缺血（5 分钟）/再灌注（5 分钟）循环。通过 H&E 染色和透射电子显微镜评估脑损伤的组织病理学特征。TUNEL 检测、免疫组织化学染色和免疫印迹用于评估神经细胞凋亡。使用 Morris 水迷宫评估学习和记忆能力。结果显示，与对照组相比，氯胺酮组大脑皮质和海马 CA1 区的 cleaved caspase-3 蛋白水平升高，细胞损伤严重，DNA 断裂，空间学习和记忆能力下降。值得注意的是，这些变化通过远程缺血预处理显著减轻。这些发现表明，远程缺血预处理可改善新生大鼠反复氯胺酮暴露后的神经细胞凋亡和神经认知障碍。
