NEUROPROTECTION BY GROWTH FACTORS DURING NO TOXICITY

神经细胞死亡，无论是由缺血或其他原因引起的， 损伤，导致长期的功能缺陷， 对生活质量的重大影响。 的直接原因 缺血性细胞死亡尚未完全了解，但很可能， 兴奋性氨基酸毒性，能量代谢的改变，以及 不能维持钙梯度各自起重要作用。 最近的研究表明，一氧化氮（NO）的产生起着重要的作用。 在兴奋性氨基酸毒性中起重要作用，而NO本身 对神经元有毒 我们已经获得了初步的数据，肽生长因子，这是 已知在正常发育和发育过程中具有营养（存活）作用， 细胞损伤的几种范式，保护海马神经元免受 缺氧或NO的毒性作用。这些观察结果表明， NO产生的不适当调节对于缺血性 神经元死亡 这也表明肽生长因子是 保护性，因为它们赋予对NO的抗性，尽管它们可能 减少NO的产生。 这一建议的四个目标是：（1）证实这一想法， 由缺氧或低血糖引起的细胞死亡是由 NO的产生; 2）确认肽生长的初步数据， 3）探讨NO诱导的细胞死亡的机制， 肽类生长因子对抗NO的分子机制 通过确定哪些信号转导系统是必不可少的 肽生长因子的保护作用; 4）确定 生长因子是否也通过减少 缺氧或低血糖损伤后NO产生的速率。 这项拨款有两个长期目标：1）更好地了解 NO在缺血诱导的细胞死亡中的作用; 2）了解 生长肽神经保护作用的生化机制 因素 这两个目标将为 缺血和其他神经退行性疾病的治疗方法的发展 阿尔茨海默病或帕金森病等疾病。

Neuronal cell death, whether it is caused by ischemia or by other insults, results in long term functional deficits that can have substantial effects on the quality of life. The immediate cause(s) of ischemic cell death are not completely understood, but it is likely that excitatory amino acid toxicity, alterations in energy metabolism, and an inability to maintain calcium gradients each plays a significant role. Recent work has shown that nitric oxide (NO) production plays an essential role in excitatory amino acid toxicity, and that NO is itself toxic to neurons. We have obtained preliminary data that peptide growth factors, which are known to have a trophic (survival) effect in normal development and in several paradigms of cell injury, protect hippocampal neurons from the toxic effects of either anoxia or NO. These observations suggest that inappropriate regulation of NO production is essential for ischemic neuronal death. It also suggests that peptide growth factors are protective because they confer a resistance to NO , although they may also reduce NO production. The four objectives of this proposal are 1) to substantiate the idea that cell death resulting from anoxia or hypoglycemia is mediated by the production of NO; 2) to confirm preliminary data that peptide growth factors can protect against NO-induced cell death; 3) to explore the molecular mechanisms by which peptide growth factors protect against NO toxicity by determining which signal transduction systems are essential for the protective effects of the peptide growth factors; 4) to determine whether growth factors also exert a protective effect by decreasing the rate of NO production after an anoxic or hypoglycemic insult. This grant has two long term objectives: 1) to better understand the role of NO in ischemia induced cell death, and 2) to understand the biochemical mechanisms of the neuroprotective effect of peptide growth factors. Both of these objectives will provide the foundation for the development of therapies for ischemia and for other neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.