FUNCTIONS OF CHOLINESTERASES IN HYPOXIA INDUCED BRAIN DAMAGE AND AMNESIA

缺氧会导致神经元丧失，包括对海马体的不可逆损伤，以及永久性记忆缺陷。然而，研究表明，在缺氧之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，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。本研究计划的目的是了解乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）在保护缺氧诱导的神经元损失和健忘症中的作用。以往研究的一个不足是没有确定AChE或BChE的具体作用。该研究的具体目的是确定抗缺氧保护是由乙酰胆碱酯酶抑制还是BChE抑制最有效地介导，或两者兼而有之。实验一旨在建立可靠的一氧化碳和亚硝酸钠诱导大鼠缺氧模型。海马和皮质细胞色素氧化酶活性的降低将用于测量缺氧诱导的神经元丢失，相关的健忘症将通过径向臂迷宫任务来测量。实验二将确定在缺氧前使用AChE或BChE选择性抑制剂治疗可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AChE或BChE选择性抑制剂是否可以减少或预防缺氧引起的损伤。这些实验结果将有助于合理制定治疗脑缺氧和缺血的新策略。

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.