LITHIUM ATTENUATES BUPIVACAINE-INDUCED NEUROTOXICITY IN VITRO THROUGH PHOSPHATIDYLINOSITOL-3-KINASE/THREONINE-SERINE PROTEIN KINASE B- AND EXTRACELLULAR SIGNAL-REGULATED KINASE-DEPENDENT MECHANISMS
LITHIUM ATTENUATES BUPIVACAINE-INDUCED NEUROTOXICITY IN VITRO THROUGH PHOSPHATIDYLINOSITOL-3-KINASE/THREONINE-SERINE PROTEIN KINASE B- AND EXTRACELLULAR SIGNAL-REGULATED KINASE-DEPENDENT MECHANISMS
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DOI：
10.1016/j.neuroscience.2011.12.043
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发表时间：
2012-03-29
期刊：
影响因子：
3.3
通讯作者：
Ding, Z.
中科院分区：
文献类型：
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作者：
Wang, Z.;Shen, J.;Ding, Z.
局部麻醉剂 (LA) 对于区域麻醉、脊髓麻醉和疼痛管理是必需的。然而，LAs的应用可能会引起神经毒性并导致术后神经系统并发症。锂是一种用于治疗双相情感障碍的情绪稳定剂，并可能发挥神经保护作用。在这项研究中，我们评估了锂对布比卡因（一种常用的 LA）引起的小鼠神经母细胞瘤神经 2a (N2a) 细胞损伤的影响。在存在或不存在锂的情况下用布比卡因处理 N2a 细胞。治疗后，通过检查活力、形态变化和核浓缩来评估细胞损伤。还检查了线粒体跨膜电位 (Delta Psi m) 的水平以及磷脂酰肌醇-3-激酶 (PI3K)/苏氨酸-丝氨酸蛋白激酶 B (Akt) 和细胞外信号调节激酶 (ERK) 的激活。在另一项实验中，我们研究了布比卡因和锂治疗后 Akt 和 ERK 抑制对细胞损伤的影响。用锂预处理 N2a 细胞可显着减轻布比卡因诱导的细胞损伤。锂预处理完全逆转了 PI3K/Akt 和 ERK 信号传导的抑制，并显着阻止了布比卡因处理后 N2a 细胞中 Delta Psi m 的下降。更重要的是，Akt 和 ERK 的药理抑制作用减弱了锂对布比卡因诱导的神经元死亡的保护作用。我们的数据表明，锂预处理对布比卡因诱导的神经元细胞损伤具有保护作用。锂的这种作用至少部分是通过激活 PI3K/Akt 和 ERK 依赖性机制来介导的。由于锂是一种经临床证明对神经元安全的药物，因此在临床实践中确定 LAs 与锂的共同给药是否会降低 LAs 引起的术后神经并发症的风险是值得的。 (C) 2012 年由 Elsevier Ltd 代表 IBRO 发布。
Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (Delta Psi m) and activation of phosphatidylinositol-3-kinase (PI3K)/threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of Delta Psi m in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice. (C) 2012 Published by Elsevier Ltd on behalf of IBRO.