Cholinesterase inhibitors: new roles and therapeutic alternatives
Cholinesterase inhibitors: new roles and therapeutic alternatives
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DOI：
10.1016/j.phrs.2003.11.017
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发表时间：
2004-10-01
影响因子：
9.3
通讯作者：
Giacobini, E
中科院分区：
文献类型：
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作者：
Giacobini, E
脑胆碱酯酶功能的一个重要方面与酶的差异有关。哺乳动物的大脑含有两种主要形式的胆碱酯酶：乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）。这两种形式在遗传、结构和动力学上都不同。丁酰胆碱不是哺乳动物脑内的生理底物，这使得BuChE的功能难以解释。在人脑中，BuChE存在于神经元和神经胶质细胞以及阿尔茨海默病（AD）患者的神经炎斑块和神经缠结中。虽然AD患者脑中AChE活性进行性降低，但BuChE活性显示出一定程度的增加。为了研究BuChE的功能，我们用选择性BuChE抑制剂对大鼠大脑进行皮质内灌注，发现细胞外乙酰胆碱从5至75 nM浓度增加了15倍，在动物中几乎没有胆碱能副作用。基于这些数据和临床数据显示CSF BuChE抑制和AD患者的认知功能之间的关系，我们假设两个池的胆碱酯酶可能存在于大脑中，第一个主要是神经元和乙酰胆碱酯酶依赖性和第二个主要是神经胶质和BuChE依赖性。这两个池显示不同的动力学特性方面的调节乙酰胆碱浓度在大脑中，可以分离的选择性抑制剂。在特定情况下，如AChE缺失的小鼠或AD晚期患者，BuChE可替代AChE水解脑内乙酰胆碱，根据AD患者脑内ChE活性的变化，选择性BuChE（或混合双功能抑制剂）治疗AD晚期患者是一个合理的适应证。ChEI治疗的第二个新方面是新适应症的出现，其包括各种形式的痴呆，例如路易体痴呆、唐氏综合征、血管性痴呆和帕金森痴呆。临床结果证明了胆碱能增强的多功能性的例子。(C)2004 Elsevier Ltd.保留所有权利。
An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases:acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75 nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine.Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement. (C) 2004 Elsevier Ltd. All rights reserved.