Haller Ingrid, Hausott Barbara, Tomaselli Bettina, Keller Christian, Klimaschewski Lars, Gerner Peter, Lirk Philipp
Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Anesthesiology. 2006 Nov;105(5):1024-33. doi: 10.1097/00000542-200611000-00025.
Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways.
The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity.
All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures.
Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.
p38丝裂原活化蛋白激酶（MAPK）的药理学抑制可导致利多卡因在体外和体内的神经毒性降低。本研究在体外探讨了以下假设：利多卡因神经毒性对不同大小或表型的背根神经节细胞具有特异性，涉及p38 MAPK的时间依赖性和特异性激活，p38 MAPK抑制剂仅在与局部麻醉剂联合应用时有效，且p38 MAPK激活触发脂氧合酶途径的激活。
作者使用原代感觉神经元培养物和嗜铬细胞瘤细胞系培养物来检测p38 MAPK或相关途径（如细胞外信号调节激酶和c-jun氨基末端激酶）的时间依赖性激活。细胞按大小或对降钙素基因相关肽或异凝集素B4的免疫反应性进行划分，降钙素基因相关肽或异凝集素B4可指示伤害性表型。作者还研究了花生四烯酸途径是否代表p38 MAPK在局部麻醉剂诱导的神经毒性中的下游效应器。
所有类型的背根神经节细胞均受到利多卡因的神经毒性作用，这是由p38 MAPK的特异性激活介导的，而非细胞外信号调节激酶或c-jun氨基末端激酶。利多卡因暴露后1小时以上给予p38 MAPK抑制剂，其神经保护功效显著下降。p38 MAPK的激活先于花生四烯酸途径的激活。利多卡因的神经毒性、p38 MAPK的特异性激活以及p38 MAPK抑制剂的神经保护作用在嗜铬细胞瘤细胞系培养物中得到进一步证实。
p38 MAPK的特异性和时间依赖性激活参与利多卡因诱导的神经毒性，最有可能随后是脂氧合酶途径的激活。
