NEUROPROTECTION BY GROWTH FACTORS DURING NO TOXICITY

神经细胞死亡，无论是由缺血还是由其他原因引起 侮辱，导致长期的功能缺陷 对生活质量有实质性的影响。的直接原因(S) 缺血性细胞死亡尚不完全清楚，但很可能是 兴奋性氨基酸毒性，能量代谢的改变，以及 不能维持钙的梯度都起着重要的作用。 最近的研究表明，一氧化氮(NO)的产生在 在兴奋性氨基酸毒性中起重要作用，而NO本身 对神经元有毒性。 我们已经获得了初步数据，这些多肽生长因子是 已知在正常发育和 几种细胞损伤的范例，保护海马神经元免受 缺氧或一氧化氮的毒性作用。这些观察结果表明 NO产生的不适当调节在缺血性脑缺血中是必不可少的 神经元死亡。它还表明，多肽生长因子是 保护性的，因为他们对NO有抵抗力，尽管他们可能 也减少了NO的生产。 这项提案的四个目标是：1)证实这样的想法 缺氧或低血糖引起的细胞死亡是由 NO；2)生产以确认多肽生长的初步数据 因子对NO诱导的细胞死亡具有保护作用；3)探索 多肽生长因子保护NO的分子机制 通过确定哪些信号转导系统是必不可少的来确定毒性 用于多肽生长因子的保护作用；4)测定 生长因子是否也起到了保护作用 缺氧或低血糖侮辱后产生NO的速率。 这笔赠款有两个长期目标：1)更好地理解 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 各种因素。这两个目标都将为 脑缺血和其他神经退行性疾病的治疗进展 阿尔茨海默氏症或帕金森氏症等疾病。

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.