Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure.
Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure.
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DOI：
10.1016/j.freeradbiomed.2015.05.029
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发表时间：
2015-09
影响因子：
7.4
通讯作者：
Levy RJ
中科院分区：
文献类型：
--
作者：
Cheng Y;Mitchell-Flack MJ;Wang A;Levy RJ
常用的麻醉剂通过氧化应激相关的线粒体凋亡途径诱导发育中的哺乳动物脑中广泛的神经元变性。细胞色素氧化酶（CcOX）（电子传递链的末端氧化酶）的调节异常可导致活性氧（ROS）形成，之前已证明异氟烷可激活该酶。一氧化碳（CO）作为CcOX的调节剂，是令人感兴趣的，因为婴儿和儿童在低流量麻醉期间常规暴露于CO。我们最近证明，低浓度的CO限制和防止异氟烷诱导的新生小鼠前脑神经毒性的剂量依赖性方式。然而，在麻醉诱导的氧化应激的背景下，CO对CcOX的影响是未知的。将7日龄雄性CD-1小鼠暴露于含0 ppm（空气）、5 ppm或100 ppm CO的空气（含或不含异氟烷）中1小时。暴露于异氟烷或CO独立增加CcOX动力学活性和增加ROS内前脑线粒体。然而，CO与异氟烷的联合暴露矛盾地限制了CcOX活化和氧化应激。CcOX I蛋白的稳态水平没有变化，表明CcOX的翻译后修饰是酶活性变化的病因。CO暴露导致CcOX亚基I酪氨酸磷酸化的差异效应取决于浓度，而异氟烷与CO联合暴露显着增加酶磷酸化状态。已显示CcOX亚基I的酪氨酸304的磷酸化导致强烈的酶抑制，并且在CO与异氟烷组合暴露后CcOX动力学的相对降低可能部分是由于这种磷酸化。综上所述，数据表明，在异氟烷暴露期间，CO调节发育中大脑中的CcOX，从而限制氧化应激。这些CO介导的作用可能对婴儿和儿童低流量麻醉的发展有影响，以防止麻醉诱导的氧化应激。
Commonly used anesthetics induce widespread neuronal degeneration in the developing mammalian brain via the oxidative stress-associated mitochondrial apoptosis pathway. Dysregulation of cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, can result in reactive oxygen species (ROS) formation and isoflurane has previously been shown to activate this enzyme. Carbon monoxide (CO), as a modulator of CcOX, is of interest because infants and children are routinely exposed to CO during low-flow anesthesia. We have recently demonstrated that low concentrations of CO limit and prevent isoflurane-induced neurotoxicity in the forebrain of newborn mice in a dose-dependent manner. However, the effect of CO on CcOX in the context of anesthetic-induced oxidative stress is unknown. Seven day old male CD-1 mice underwent 1-hour exposure to 0 ppm (air), 5 ppm, or 100 ppm CO in air with or without isoflurane. Exposure to isoflurane or CO independently increased CcOX kinetic activity and increased ROS within forebrain mitochondria. However, combined exposure to CO with isoflurane paradoxically limited CcOX activation and oxidative stress. There were no changes seen in steady-state levels of CcOX I protein indicating post-translational modification of CcOX as an etiology for changes in enzyme activity. CO exposure led to differential effects on CcOX subunit I tyrosine phosphorylation depending on concentration, while combined exposure to isoflurane with CO markedly increased enzyme phosphorylation state. Phosphorylation of tyrosine 304 of CcOX subunit I has been shown to result in strong enzyme inhibition, and the relative reduction in CcOX kinetics following combined exposure to CO with isoflurane may have been due, in part, to such phosphorylation. Taken together, the data suggest that CO modulates CcOX in the developing brain during isoflurane exposure, thereby limiting oxidative stress. These CO-mediated effects could have implications for the development of low-flow anesthesia in infants and children in order to prevent anesthesia-induced oxidative stress.