FUNCTIONS OF CHOLINESTERASES IN HYPOXIA INDUCED BRAIN DAMAGE AND AMNESIA

胆碱酯酶在缺氧引起的脑损伤和健忘症中的作用

• 批准号: 6325816
• 负责人: donald e moss
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325816
• 关键词: acetylcholinesterase; brain injury; carboxyhemoglobin; cell death; cellular pathology; cerebral ischemia /hypoxia; cholinesterase inhibitors; cholinesterases; cytochrome oxidase; cytoprotection; enzyme activity; laboratory rat; long term memory; memory disorders; methemoglobin; neurons; short term memory; statistics /biometry

Hypoxia causes neuronal loss, including irreversible damage to the hippocampus, and permanent memory deficiencies. However, it has been shown that short-term treatment with a cholinesterase inhibitor before or immediately after hypoxia prevents at least some of the neuronal loss and this treatment can change the long-term outcome, preserving both the the neuronal tissue and cognitive function. The objective of this research program is to understand the contributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in protecting against hypoxia-induced neuronal losses and amnesia. A weakness in the previous research is that the specific role of AChE or BChE was not determined. The specific aim of the research is to determine if protection against hypoxia is most effectively mediated by AChE or BChE inhibition, or both. Experiment One will establish a reliable model of carbon monoxide (CO) and sodium nitrite (SN) induced hypoxia in rats. Reductions of cytochrome oxidase activity in the hippocampus and cortex will be used to measured hypoxia-induced neuronal loss and the correlated amnesia will be measured by a radial arm maze task. Experiment Two will determine to what extent hypoxia-induced changes can be prevented with treatment of selective inhibitors of AChE or BChE before hypoxia. Experiment three will determine whether or not treatment with selective inhibitors of AChE or BChE given after hypoxia can reduce or prevent hypoxia-induced damage. The results of these experiments will assist in the rational development of new strategies for treating brain hypoxia and ischemia.

缺氧会导致神经元损失，包括对海马体的不可逆损伤和永久性记忆缺陷。然而，研究表明，在缺氧之前或之后立即使用胆碱酯酶抑制剂进行短期治疗至少可以防止部分神经元损失，并且这种治疗可以改变长期结果，保留神经元组织和认知功能。该研究计划的目的是了解乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 在防止缺氧引起的神经元损失和健忘症方面的贡献。先前研究的一个弱点是AChE或BChE的具体作用尚未确定。该研究的具体目的是确定 AChE 或 BChE 抑制或两者均能最有效地介导缺氧。实验一将建立可靠的一氧化碳（CO）和亚硝酸钠（SN）诱导的大鼠缺氧模型。海马和皮质中细胞色素氧化酶活性的降低将用于测量缺氧引起的神经元损失，并且将通过放射臂迷宫任务测量相关的遗忘症。实验二将确定在缺氧前使用选择性 AChE 或 BChE 抑制剂治疗可以在多大程度上预防缺氧引起的变化。实验三将确定缺氧后给予选择性 AChE 或 BChE 抑制剂治疗是否可以减少或预防缺氧引起的损伤。这些实验的结果将有助于合理开发治疗脑缺氧和缺血的新策略。