Liu Fang, Rainosek Shuo W, Sadovova Natalya, Fogle Charles M, Patterson Tucker A, Hanig Joseph P, Paule Merle G, Slikker William, Wang Cheng
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079, USA.
Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Neurotoxicology. 2014 May;42:49-57. doi: 10.1016/j.neuro.2014.03.011. Epub 2014 Apr 2.
Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology. Acetyl-L-carnitine (L-Ca), an anti-oxidant dietary supplement, has been reported to prevent neuronal damage from a variety of causes. To evaluate the ability of L-Ca to protect against propofol-induced neuronal toxicity, neural stem cells were isolated from gestational day 14 rat fetuses and on the eighth day in culture were exposed for 24h to propofol at 10, 50, 100, 300 and 600 μM, with or without L-Ca (10 μM). Markers of cellular proliferation, mitochondrial health, cell death/damage and oxidative damage were monitored to determine: (1) the effects of propofol on neural stem cell proliferation; (2) the nature of propofol-induced neurotoxicity; (3) the degree of protection afforded by L-Ca; and (4) to provide information regarding possible mechanisms underlying protection. After propofol exposure at a clinically relevant concentration (50 μM), the number of dividing cells was significantly decreased, oxidative DNA damage was increased and a significant dose-dependent reduction in mitochondrial function/health was observed. No significant effect on lactase dehydrogenase (LDH) release was observed at propofol concentrations up to 100 μM. The oxidative damage at 50 μM propofol was blocked by L-Ca. Thus, clinically relevant concentrations of propofol induce dose-dependent adverse effects on rat embryonic neural stem cells by slowing or stopping cell division/proliferation and causing cellular damage. Elevated levels of 8-oxoguanine suggest enhanced oxidative damage [reactive oxygen species (ROS) generation] and L-Ca effectively blocks at least some of the toxicity of propofol, presumably by scavenging oxidative species and/or reducing their production.
丙泊酚是一种广泛使用的全身麻醉剂。越来越多的数据表明，围产期接触全身麻醉剂会对脑功能产生长期有害影响。在发育中的大脑中，有证据表明全身麻醉剂可导致细胞死亡、突触重塑和脑细胞形态改变。乙酰-L-肉碱（L-Ca）是一种抗氧化膳食补充剂，据报道可预防多种原因引起的神经元损伤。为了评估L-Ca预防丙泊酚诱导的神经元毒性的能力，从妊娠第14天的大鼠胎儿中分离神经干细胞，并在培养的第8天将其暴露于10、50、100、300和600μM的丙泊酚中24小时，添加或不添加L-Ca（10μM）。监测细胞增殖、线粒体健康、细胞死亡/损伤和氧化损伤的标志物，以确定：（1）丙泊酚对神经干细胞增殖的影响；（2）丙泊酚诱导的神经毒性的性质；（3）L-Ca提供的保护程度；（4）提供有关保护潜在机制的信息。在临床相关浓度（50μM）的丙泊酚暴露后，分裂细胞数量显著减少，氧化性DNA损伤增加，并且观察到线粒体功能/健康显著的剂量依赖性降低。在丙泊酚浓度高达100μM时，未观察到对乳酸脱氢酶（LDH）释放有显著影响。50μM丙泊酚引起的氧化损伤被L-Ca阻断。因此，临床相关浓度的丙泊酚通过减缓或停止细胞分裂/增殖并导致细胞损伤，对大鼠胚胎神经干细胞产生剂量依赖性不良反应。8-氧代鸟嘌呤水平升高表明氧化性损伤增强[活性氧（ROS）生成]，并且L-Ca有效地阻断了丙泊酚的至少一些毒性，大概是通过清除氧化物质和/或减少其产生。
