Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury.
Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury.
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DOI：
10.1016/j.expneurol.2009.04.030
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Fiskum, Gary
中科院分区：
文献类型：
--
作者：
Robertson, Courtney L.;Scafidi, Susanna;McKenna, Mary C.;Fiskum, Gary
关键词：
有几种形式的急性小儿脑损伤，包括新生儿窒息，小儿心脏骤停与全脑缺血，头部创伤，导致毁灭性的，终身的神经功能障碍。唯一具有神经保护作用的临床干预措施是在最初受伤后不久开始的低温治疗。有证据表明，氧化应激、线粒体功能障碍和脑能量代谢受损导致脑细胞死亡，这是这些事件导致神经功能不良的主要原因。从未成熟脑中神经元死亡的体外和动物模型获得的最新结果指向由大分子的氧化修饰诱导或促进的几种分子机制，包括通过聚ADP核糖聚合酶消耗胞质和线粒体NAD+，打开线粒体内膜通透性转换孔，以及关键限速代谢酶的失活，例如，丙酮酸脱氢酶复合物。此外，在未成熟的脑和神经元中，特别是在它们的线粒体内，促凋亡蛋白的相对丰度使这些细胞倾向于凋亡的内在线粒体途径，该途径由Bax或Bak触发的蛋白质通过线粒体外膜释放到胞质溶胶中介导。基于这些细胞功能障碍和死亡的途径，正在研究几种神经保护方法，这些方法显示出临床转化的前景。这些策略包括通过避免不必要的高氧来最小化氧化应激，通过补充NAD+和通过提供替代氧化燃料来促进有氧能量代谢，例如，酮体，直接干扰线粒体水平的凋亡途径，以及抗氧化剂和抗炎基因表达的药理学诱导。
There are several forms of acute pediatric brain injury, including neonatal asphyxia, pediatric cardiac arrest with global ischemia, and head trauma, that result in devastating, lifelong neurologic impairment. The only clinical intervention that appears neuroprotective is hypothermia initiated soon after the initial injury. Evidence indicates that oxidative stress, mitochondrial dysfunction, and impaired cerebral energy metabolism contribute to the brain cell death that is responsible for much of the poor neurologic outcome from these events. Recent results obtained from both in vitro and animal models of neuronal death in the immature brain point toward several molecular mechanisms that are either induced or promoted by oxidative modification of macromolecules, including consumption of cytosolic and mitochondrial NAD+ by poly-ADP ribose polymerase, opening of the mitochondrial inner membrane permeability transition pore, and inactivation of key, rate-limiting metabolic enzymes, e.g., the pyruvate dehydrogenase complex. In addition, the relative abundance of pro-apoptotic proteins in immature brains and neurons, and particularly within their mitochondria, predisposes these cells to the intrinsic, mitochondrial pathway of apoptosis, mediated by Bax- or Bak-triggered release of proteins into the cytosol through the mitochondrial outer membrane. Based on these pathways of cell dysfunction and death, several approaches toward neuroprotection are being investigated that show promise toward clinical translation. These strategies include minimizing oxidative stress by avoiding unnecessary hyperoxia, promoting aerobic energy metabolism by repletion of NAD+ and by providing alternative oxidative fuels, e.g., ketone bodies, directly interfering with apoptotic pathways at the mitochondrial level, and pharmacologic induction of antioxidant and anti-inflammatory gene expression.
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影响因子：
2.9
作者：
Adcock, KH;Nedelcu, J;Wagner, BP
通讯作者：
Wagner, BP
影响因子：
4.2
作者：
Alessandri, B;Rice, AC;Bullock, MR
通讯作者：
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影响因子：
2.4
作者：
Azzopardi D;Brocklehurst P;Edwards D;Halliday H;Levene M;Thoresen M;Whitelaw A;TOBY Study Group
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TOBY Study Group
影响因子：
158.5
作者：
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通讯作者：
Smith, K
影响因子：
4.1
作者：
Ahn, Edward S.;Robertson, Courtney L.;Fiskum, Gary
通讯作者：
Fiskum, Gary