Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, People's Republic of China.
Fujian Provincial Institute of Emergency Medicine, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, People's Republic of China.
Neurotox Res. 2021 Apr;39(2):133-145. doi: 10.1007/s12640-020-00299-6. Epub 2020 Nov 6.
Amitriptyline (AMI) is a traditional tricyclic antidepressant that has been proven to exhibit neuroprotective effects in various neurological disorders. However, the underlying mechanism by which AMI attenuates lidocaine-induced neurotoxicity remains poorly understood. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin to neuronal development and survival in the brain, and recent studies have suggested that BDNF plays an important role in mediating lidocaine-induced neurotoxicity. The present study was performed to evaluate the protective effect of AMI against the neurotoxicity induced by lidocaine and to explore the role of BDNF-dependent autophagy in this process. The data showed that AMI pretreatment alleviated lidocaine-induced neurotoxicity, as evidenced by the restoration of cell viability, normalization of cell morphology, and reduction in the cell apoptosis index. In addition, autophagy inhibitor 3-methyladenine (3-MA) had a protective effect similar to that of AMI, but autophagy activator rapamycin eliminated the protective effect of AMI by suppressing mTOR activation. Moreover, at the molecular level, we found that AMI-mediated autophagy was involved in the expression of BDNF. The overexpression of BDNF or application of exogenous recombinant BDNF significantly suppressed autophagy and protected SH-SY5Y cells from apoptosis induced by Lido, whereas the neuroprotection of AMI was abolished by either knockdown of BDNF or use of a tropomyosin-related kinase B (TrkB) inhibitor ANA-12 in SH-SY5Y cells. Overall, our findings demonstrated that the protective effect of AMI against lidocaine-induced neurotoxicity correlated with inhibition of autophagy activity through upregulation of BDNF expression.
阿米替林（AMI）是一种传统的三环抗抑郁药，已被证明在各种神经疾病中具有神经保护作用。然而，AMI 减轻利多卡因诱导的神经毒性的潜在机制仍知之甚少。脑源性神经营养因子（BDNF）是大脑中神经元发育和存活所必需的神经营养因子，最近的研究表明，BDNF 在介导利多卡因诱导的神经毒性中发挥重要作用。本研究旨在评估 AMI 对利多卡因诱导的神经毒性的保护作用，并探讨 BDNF 依赖性自噬在此过程中的作用。研究数据表明，AMI 预处理可减轻利多卡因诱导的神经毒性，表现为细胞活力的恢复、细胞形态的正常化和细胞凋亡指数的降低。此外，自噬抑制剂 3-甲基腺嘌呤（3-MA）具有与 AMI 相似的保护作用，但自噬激活剂雷帕霉素通过抑制 mTOR 激活消除了 AMI 的保护作用。此外，在分子水平上，我们发现 AMI 介导的自噬参与了 BDNF 的表达。BDNF 的过表达或外源性重组 BDNF 的应用显著抑制自噬并保护 SH-SY5Y 细胞免受 Lido 诱导的凋亡，而 AMI 的神经保护作用被 SH-SY5Y 细胞中的 BDNF 敲低或 tropomyosin-related kinase B (TrkB) 抑制剂 ANA-12 消除。总之，我们的研究结果表明，AMI 对利多卡因诱导的神经毒性的保护作用与通过上调 BDNF 表达抑制自噬活性有关。
