EXCITATORY AMINO ACIDS AND HYPOXIC DAMAGE IN THE CNS

中枢神经系统的兴奋性氨基酸和缺氧损伤

• 批准号: 3083812
• 负责人: JAMES E MADL
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-14 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3083812
• 关键词: chick embryo; cysteine; electron microscopy; glutamate receptor; hypoxia; laboratory mouse; laboratory rat; monoclonal antibody; neuroanatomy; neurons; neurotransmitters; retinal ganglion; synapses; taurine; tissue /cell culture

The overall goal of this research is to analyze the immunocytochemical distribution of putative excitatory amino acid neurotransmitters in the retina and to relate this distribution to that of neuronal susceptibility to hypoxic damage. An abundance of evidence implicates excitatory amino acids and their analogs as toxins in the CNS including the retina. Recent studies in vivo and in vitro indicate that hypoxic neuronal damage requires the synaptic release of excitatory amino acids and that hypoxic or ischemic neuronal death can be prevented by the administration of excitatory amino acid antagonists. Very large increases in the extracellular concentrations of glutamate and aspartate have been measured in the hippocampus within minutes of the induction of ischemia. Our proposed investigations of the role of putative excitatory amino acids in hypoxic neuronal lesions are described by the following specific aims: (1) To develop monoclonal antibodies with high specificity for cysteine sulfinate, cysteate and taurine using methods similar to those we have previously employed to raise monoclonal antibodies highly specific for fixative-modified glutamate and aspartate. (2) To determine the specific location in the retina of intense immunoreactivity for these monoclonal antibodies using both light and electron microscopy. (3) To combine and modify two existing models (for glutamate toxicity in retina and hypoxic damage in hippocampal neuronal culture) and thereby develop a new model for neuronal hypoxia using cultured embryonic chick retina and demonstrate that retinal neurons selectively susceptible to hypoxic damage have synaptic input from neurons with intense excitatory amino acid immunoreactivity. (4) To investigate the possible protection of neurons from hypoxic damage in this model system by administration of excitatory amino acid antagonists. These studies will test the clinically important concept that specific excitatory amino acids are in high concentrations at synapses upon neurons that are selectively sensitive to hypoxic damage.

本研究的总体目标是分析免疫细胞化学