Lei B, Popp S, Capuano-Waters C, Cottrell J E, Kass I S
Department of Anesthesiology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Neuroscience. 2004;125(3):691-701. doi: 10.1016/j.neuroscience.2004.02.034.
Lidocaine is a local anesthetic and antiarrhythmic agent. Although clinical and experimental studies have shown that an antiarrhythmic dose of lidocaine can protect the brain from ischemic damage, the underlying mechanisms are unknown. In the present study, we examined whether lidocaine inhibits neuronal apoptosis in the penumbra in a rat model of transient focal cerebral ischemia. Male Wistar rats underwent a 90-min temporary occlusion of middle cerebral artery. Lidocaine was given as an i.v. bolus (1.5 mg/kg) followed by an i.v. infusion (2 mg/kg/h) for 180 min, starting 30 min before ischemia. Rats were killed and brain samples were collected at 4 and 24 h after ischemia. Apoptotic changes were evaluated by immunohistochemistry for cytochrome c release and caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) for DNA fragmentation. Cytochrome c release and caspase-3 activation were detected at 4 and 24 h after ischemia and DNA fragmentation was detected at 24 h. Double-labeling with NeuN, a neuronal marker, demonstrated that cytochrome c, caspase-3, and TUNEL were confined to neurons. Lidocaine reduced cytochrome c release and caspase-3 activation in the penumbra at 4 h and diminished DNA fragmentation in the penumbra at 24 h. Lidocaine treatment improved early electrophysiological recovery and reduced the size of the cortical infarct at 24 h, but had no significant effect on cerebral blood flow in either the penumbra or core during ischemia. These findings suggest that lidocaine attenuates apoptosis in the penumbra after transient focal cerebral ischemia. The infarct-reducing effects of lidocaine may be due, in part, to the inhibition of apoptotic cell death in the penumbra.
利多卡因是一种局部麻醉药和抗心律失常药。尽管临床和实验研究表明，抗心律失常剂量的利多卡因可保护大脑免受缺血性损伤，但其潜在机制尚不清楚。在本研究中，我们检测了利多卡因是否能抑制短暂性局灶性脑缺血大鼠模型半暗带中的神经元凋亡。雄性Wistar大鼠接受大脑中动脉90分钟的临时闭塞。在缺血前30分钟开始，静脉推注利多卡因（1.5mg/kg），随后静脉输注（2mg/kg/h）持续180分钟。在缺血后4小时和24小时处死大鼠并收集脑样本。通过免疫组织化学检测细胞色素c释放和半胱天冬酶-3激活来评估凋亡变化，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）检测DNA片段化。在缺血后4小时和24小时检测到细胞色素c释放和半胱天冬酶-3激活，在24小时检测到DNA片段化。用神经元标志物NeuN进行双重标记表明，细胞色素c、半胱天冬酶-3和TUNEL仅限于神经元。利多卡因在4小时时减少了半暗带中细胞色素c的释放和半胱天冬酶-3的激活，并在24小时时减少了半暗带中的DNA片段化。利多卡因治疗改善了早期电生理恢复，并在24小时时减小了皮质梗死灶的大小，但在缺血期间对半暗带或梗死核心的脑血流量没有显著影响。这些发现表明，利多卡因可减轻短暂性局灶性脑缺血后半暗带中的凋亡。利多卡因的梗死灶缩小作用可能部分归因于对半暗带中凋亡细胞死亡的抑制。
