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.
