Mitochondrial injury and caspase activation by the local anesthetic lidocaine
Mitochondrial injury and caspase activation by the local anesthetic lidocaine
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DOI：
10.1097/00000542-200411000-00019
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发表时间：
2004-11-01
期刊：
影响因子：
8.8
通讯作者：
Gores, GJ
中科院分区：
文献类型：
--
作者：
Johnson, ME;Uhl, CB;Gores, GJ
背景：利多卡因是一种局部麻醉剂，可能会产生神经毒性。然而，其神经毒性的细胞机制尚不清楚。方法：研究利多卡因对大鼠背根神经节ND7细胞的神经毒性作用机制。结果：在ND7细胞系中，185 mm×10min~2.3 mm×24 h的利多卡因可引起细胞坏死或晚期凋亡。等摩尔Tris缓冲液和等效河豚毒素对照组均无毒性，表明渗透压或钠离子阻断效应均不能解释利多卡因的神经毒性。利多卡因神经毒性的最早表现是在19 mM或更大浓度的利多卡因作用后5分钟内线粒体膜电位完全丧失。与此相一致的是，37 mM利多卡因(1%)可诱导线粒体细胞色素c释放到细胞质中，并导致质膜起泡、磷脂酰丝氨酸膜不对称性丧失和caspase激活，线粒体细胞色素c在2 h内释放到细胞质中。caspase特异性抑制剂z-VAD-fmk可阻止caspase激活，延缓但不能阻止神经元死亡，但不能抑制其他凋亡指标。结论：综合而言，利多卡因神经毒性涉及线粒体功能障碍和细胞凋亡途径的激活。
Background: Lidocaine, a local anesthetic, can be neurotoxic. However, the cellular mechanisms of its neurotoxicity at concentrations encountered during spinal anesthesia remain unclear.Methods: The authors examined the mechanisms of lidocaine neurotoxicity in the ND7 cell fine derived from rat dorsal root ganglion. Individual neurons were assayed by flow cytometry or microscopy using fluorescent probes of plasma membrane integrity, mitochondrial membrane potential, caspase activity, phosphotipid membrane asymmetry, and mitochondrial cytochrome c release.Results: In the ND7 cell line, lidocaine at 185 mm x 10 min to 2.3 mm x 24 h caused necrosis or late apoptosis. Equimolar Tris buffer and equipotent tetrodotoxin controls were not toxic, indicating that neither osmotic nor Na+-blocking effects explain lidocaine neurotoxicity. The earliest manifestation of lidocaine neurotoxicity was complete loss of mitochondrial membrane potential within 5 min after exposure to lidocaine at a concentration of 19 mm or greater. Consistent with these data, 37 mm lidocaine (1%) induced release of mitochondrial cytochrome c into the cytoplasm, as well as plasma membrane blebbing, loss of phosphatidylserine membrane asymmetry, and caspase activation, with release of mitochondrial cytochrome c to the cytoplasm within 2 h. Treatment with z-VAD-fmk, a specific inhibitor of caspases, prevented caspase activation and delayed but did not prevent neuronal death, but did not inhibit the other indicators of apoptosis.Conclusions: Collectively, these data indicate that lidocaine neurotoxicity involves mitochondrial dysfunction with activation of apoptotic pathways.