FUNCTIONS OF CHOLINESTERASES IN HYPOXIA INDUCED BRAIN DAMAGE AND AMNESIA

缺氧会导致神经元丢失，包括对海马体的不可逆转损伤，以及永久性记忆缺陷。然而，已有研究表明，在缺氧前或缺氧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丢失，这种治疗可以改变长期结果，保护神经元组织和认知功能。本研究的目的是了解乙酰胆碱酯酶(AChE)和丁基胆碱酯酶(BChE)在防止缺氧引起的神经元丢失和健忘中的作用。先前研究中的一个弱点是，AChE或BChE的具体作用尚未确定。这项研究的具体目的是确定抑制AChE或BChE，还是两者兼而有之，是最有效的抗缺氧保护作用。实验一建立一氧化碳(CO)和亚硝酸钠(SN)诱导的大鼠缺氧模型。海马区和大脑皮层细胞色素氧化酶活性的降低将被用来测量缺氧诱导的神经元丢失，相关的健忘症将通过放射状手臂迷宫任务来测量。实验二将确定在多大程度上可以在低氧前使用选择性的AChE或BChE抑制剂来预防低氧引起的改变。实验三将确定在低氧后给予选择性的AchE或BChE抑制剂治疗是否可以减少或防止低氧诱导的损伤。这些实验结果将有助于合理开发治疗脑缺氧和脑缺血的新策略。

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.