GLUTAMATE NEUROTOXICITY IN CORTICAL CELL CULTURE

提议的实验的目标是继续描述 谷氨酸神经毒性的细胞机制，一个过程 可能参与了与神经元变性相关的 某些急性或慢性神经系统疾病，包括阿尔茨海默病 疾病。即使是谷氨酸的神经毒性也不参与 任何慢性神经退行性疾病的发病机制，提出了 对其潜在机制的阐明可能会产生有价值的 对神经细胞损伤的一些常见原理的洞察。至 要实现细胞和分子分辨率，研究将需要 置于已建立的分离的小鼠皮质细胞培养模型中 系统。使用药理学、生理学和神经化学 方法，包括神经毒性分析，组织化学染色，整体 细胞记录，高效液相色谱，45Ca2积聚，Fura-2视频显微镜， 将具体寻求这四个问题的答案：1)什么是 “代谢型”谷氨酸受体在谷氨酸中的作用 神经毒性？2)钙在谷氨酸中的作用是什么 神经毒性？3)脂质过氧化在调节神经毒性中的作用 谷氨酸神经毒性？以及4)为什么皮质神经元包含 耐NMDA受体的高浓度NADPH-黄递酶- 介入性伤害？拟议中的实验将提供新的信息 关于谷氨酸的神经毒性的性质，并可能导致 旨在减少病理改变的治疗方法的发展 阿尔茨海默病或相关疾病的神经细胞死亡。

The goal of the proposed experiments is a continued characterization of the cellular mechanisms underlying glutamate neurotoxicity, a process which may participate in the neuronal degeneration associated with certain acute or chronic neurological diseases, including Alzheimer's disease. Even is glutamate neurotoxicity is not involved in the pathogenesis of any chronic neurodegenerative diseases, it is proposed that elucidation of its underlying mechanisms could yield valuable insights into some common principles of neuronal cell injury. To achieve cellular and molecular resolution, investigations will take place in an established dissociated murine cortical cell culture model system. Using pharmacological, physiological, and neurochemical approaches, including neurotoxicity assays, histochemical stains, whole cell recording, HPLC, 45Ca2+ accumulation, and fura-2 videomicroscopy, answers to these four questions will be specifically sought: 1) What is the role of the "metabotropic" glutamate receptor in glutamate neurotoxicity? 2) What is the role of calcium in glutamate neurotoxicity? 3) What is the role of lipid peroxidation in mediating glutamate neurotoxicity? and 4) Why are cortical neurons containing high concentrations of NADPH-diaphorase resistant to NMDA receptor- mediated injury? The proposed experiments will provide new information regarding the nature of glutamate neurotoxicity and could lead to the development of therapeutic approaches designed to reduce pathological neuronal cell death in Alzheimer's disease or related disorders.