Department of Anesthesiology, Hunan Children's Hospital, No.86 Ziyuan Rd, Changsha, 410007, Hunan, China.
Mol Neurobiol. 2023 Dec;60(12):7009-7020. doi: 10.1007/s12035-023-03498-2. Epub 2023 Jul 31.
Prolonged exposure to local anesthetics (LAs) or intrathecal administration of high doses of LAs can cause spinal cord damage. Intraspinal administration of LAs is increasingly being used in children and neonates. Therefore, it is important to study LA-related spinal cord damage and the underlying mechanism in developmental models. First, neonatal Sprague-Dawley rats received three intrathecal injections of 0.5% ropivacaine, 1% ropivacaine, 2% ropivacaine or saline (90-min interval) on postnatal day 7. Electron microscopy, luxol fast blue staining and behavioral tests were performed to evaluate the spinal neurotoxicity caused by ropivacaine at different concentrations. Western blot analysis and immunostaining was performed to detect the expression changes of p-Akt, Akt, myelin gene regulatory factor (MYRF) and myelin basic protein (MBP) in the spinal cord treated with different concentrations of ropivacaine. Our results showed that 1% or 2% ropivacaine impaired myelination in the spinal cord and induced sensory dysfunction, but 0.5% ropivacaine did not. Moreover, 1% or 2% ropivacaine decreased the expression of p-Akt, MYRF and MBP in the spinal cord. Then, in order to further explore the role of these proteins in this model, the Akt-specific activator (SC79) was intraperitoneally injected 30 min before 2% ropivacaine treatment. Interestingly, SC79-mediated activation of Akt partly rescued ropivacaine-induced myelination impairments and sensory dysfunction. Overall, the results showed that ropivacaine caused spinal neurotoxicity in a dose-dependent manner in neonatal rats and that activation of the Akt partly rescued ropivacaine-induced these changes. These data provide insight into the neurotoxicity to the developing spinal cord caused by LAs.
局部麻醉剂（LA）长时间暴露或鞘内给予高剂量的 LA 可导致脊髓损伤。LA 在儿童和新生儿中的鞘内给药越来越多。因此，在发育模型中研究 LA 相关的脊髓损伤及其潜在机制非常重要。首先，新生 Sprague-Dawley 大鼠在生后第 7 天接受 3 次鞘内注射 0.5%罗哌卡因、1%罗哌卡因、2%罗哌卡因或生理盐水（90 分钟间隔）。电子显微镜、卢索快速蓝染色和行为测试用于评估不同浓度罗哌卡因引起的脊髓神经毒性。Western blot 分析和免疫染色用于检测不同浓度罗哌卡因处理的脊髓中 p-Akt、Akt、髓鞘基因调节因子（MYRF）和髓鞘碱性蛋白（MBP）的表达变化。我们的结果表明，1%或 2%罗哌卡因损害脊髓的髓鞘形成并引起感觉功能障碍，但 0.5%罗哌卡因没有。此外，1%或 2%罗哌卡因降低了脊髓中 p-Akt、MYRF 和 MBP 的表达。然后，为了进一步探讨这些蛋白在该模型中的作用，在 2%罗哌卡因处理前 30 分钟经腹腔注射 Akt 特异性激活剂（SC79）。有趣的是，SC79 介导的 Akt 激活部分挽救了罗哌卡因引起的髓鞘形成损伤和感觉功能障碍。总体而言，结果表明罗哌卡因在新生大鼠中以剂量依赖的方式引起脊髓神经毒性，Akt 的激活部分挽救了罗哌卡因引起的这些变化。这些数据为 LA 引起的发育中脊髓的神经毒性提供了深入的了解。
