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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death
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Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

机译：烟酰胺单核苷酸腺苷酸转移酶1通过抑制兴奋性毒性坏死性细胞死亡来保护中枢神经系统发育中的急性神经变性

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摘要

Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-l. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnati against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnati in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-l brain injury. As early as 6 h after H-l, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-l. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-de-pendent cell death in cytNmnat1 -Tg brains. CytNmnati protected neuronal cell bodies and processes against NMDA-induced excito-toxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnati protects against neonatal Hl-induced CNS injury by inhibiting excitotoxic-ity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnati protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.
机译：发育中的大脑缺氧缺血（H-I）损伤是人类发病和死亡的重要原因。除了体温过低外，没有有效的方法可以预防或减轻新生儿H-1的后果。 NAD合成酶烟酰胺单核苷酸腺苷酸转移酶1（Nmnat1）的表达增加表明对周围神经系统的轴突损伤具有神经保护作用。为了研究Nmnati在发育中的CNS中对急性神经变性的神经保护作用，我们将野生型小鼠和细胞质中过表达Nmnati的小鼠（cytNmnat1-Tg小鼠）暴露于特征明确的新生儿H-1脑损伤模型中。早在H-1后6小时，cytNmnat1-Tg小鼠的MRI损伤明显减少。通过H-1后7天的组织体积损失评估，CytNmnat1-Tg小鼠对海马，皮层和纹状体的损伤明显少于野生型小鼠。 cytNmnat1介导的戏剧性保护作用不是通过调节cytNmnat1-Tg脑中caspase3-de-pendent细胞死亡来介导的。 CytNmnati保护神经元细胞体和过程免受NMDA诱导的兴奋性毒性，而胱天蛋白酶抑制或B细胞淋巴瘤超大蛋白（Bcl-XL）的过表达在培养的皮质神经元中没有保护作用。这些结果表明，cytNmnati通过抑制神经毒性和神经元过程的兴奋毒性诱导，caspase依赖性损伤来预防新生的H1诱导的CNS损伤。因此，Nmnati保护途径可能是兴奋性毒性介导的急性和慢性神经变性损伤的有用治疗靶标。

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  • 作者

    Philip B. Verghese; Yo Sasaki; Donghan Yang; Floy Stewart; Fatima Sabar; Mary Beth Finn; Christine M. Wroge; Steven Mennerick; Jeffrey J. Neil; Jeffrey Milbrandt; David M. Holtzman;

  • 作者单位

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110,Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of Genetics, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Chemistry, Washington University, St. Louis, MO 63130;

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110,Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110,Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of Genetics, Washington University School of Medicine, St. Louis, MO 63110;

    Departments of Neurology, Washington University School of Medicine, St. Louis, MO 63110,Departments of Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110,Departments of The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    magnetic resonance imaging; transgenic; apoptosis; necrosis;

    机译：磁共振成像转基因细胞凋亡坏死;

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