Lirk Philipp, Haller Ingrid, Myers Robert R, Klimaschewski Lars, Kau Yi-Chuan, Hung Yu-Chun, Gerner Peter
Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Austria.
Anesthesiology. 2006 Jun;104(6):1266-73. doi: 10.1097/00000542-200606000-00023.
Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic.
Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition.
Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580.
The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.
局部麻醉药引起的直接神经毒性（感觉异常、无法恢复正常感觉和运动功能）是区域麻醉潜在的毁灭性并发症。局部麻醉药激活p38丝裂原活化蛋白激酶（MAPK）系统，该系统参与凋亡性细胞死亡。因此，作者在体外（培养的初级感觉神经元）和体内（坐骨神经阻滞模型）研究了与临床用局部麻醉药（利多卡因）或研究用局部麻醉药（阿米替林）联合使用的p38 MAPK抑制剂SB203580的潜在神经保护作用。
在孵育有利多卡因或阿米替林的大鼠背根神经节中，添加或不添加SB203580，评估细胞存活和线粒体去极化作为凋亡性细胞死亡的标志物。同样，在坐骨神经阻滞模型中，作者通过光学显微镜评估沃勒变性，以检测MAPK抑制的潜在减轻作用。
40 mmol/L（约1%）的利多卡因和100 μmol/L的阿米替林可减少神经元数量，但与10 μmol/L的p38 MAPK抑制剂SB203580共同孵育可显著降低细胞毒性以及出现线粒体去极化的神经元数量。此外，SB203580似乎可减轻由利多卡因（600 mmol/L，约15%）和阿米替林（10 mmol/L，约0.3%）诱导的沃勒变性和脱髓鞘。
利多卡因和阿米替林在培养的背根神经节细胞中的细胞毒性作用以及大鼠坐骨神经模型中的神经变性似乎至少部分是由细胞凋亡介导的，但似乎可被p38 MAPK抑制剂有效阻断，这使得联合注射可能有助于预防局部麻醉药引起的神经毒性成为可能。
