Selective inhibitors of butyrylcholinesterase - A valid alternative for therapy of Alzheimer's disease?
Selective inhibitors of butyrylcholinesterase - A valid alternative for therapy of Alzheimer's disease?
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DOI：
10.2165/00002512-200118120-00001
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发表时间：
2001-01-01
期刊：
影响因子：
2.8
通讯作者：
Giacobini, E
中科院分区：
文献类型：
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作者：
Giacobini, E
哺乳动物的大脑含有两种主要形式的胆碱酯酶 (ChE)：乙酰胆碱酯酶 (ACNE) 和丁酰胆碱酯酶 (BuChE)。这两种形式在遗传、结构和动力学上有所不同。丁酰胆碱不是哺乳动物大脑中的生理底物，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) 患者的神经斑和神经缠结中。 AD患者大脑中ACNE活性逐渐降低，而BuChE活性却有所增加。为了研究BuChE的功能，我们在大鼠大脑皮质内灌注了选择性BuChE抑制剂。我们发现细胞外乙酰胆碱水平从 5 nmol/L 增加到 75 nmol/L 浓度，增加了 15 倍，并且对动物几乎没有胆碱能副作用。根据这些数据，我们假设大脑中可能存在两种 ChE 池：一种主要是神经元和 ACNE 依赖性的；另一种主要是神经元和 ACNE 依赖性的。一种主要依赖于神经胶质和BuChE。这两个池在调节大脑中的乙酰胆碱浓度方面表现出不同的动力学特性，并且可以通过选择性抑制剂进行分离。最近开发的高选择性 BuChE 抑制剂将使我们能够在 AD 患者中测试这些新药物，以确定与目前使用的选择性（多奈哌齐）或相对非选择性（卡巴拉汀、加兰他敏）ChE 抑制剂相比，它们是否代表治疗 AD 患者的优势。 BuChE-K 变异与 AD 之间的关系尚未在多项研究中得到证实。 总之，为了阐明 BuChE 在正常脑功能和 AD 患者大脑中的作用，需要进行额外的实验和临床工作。未来，选择性 BuChE 抑制剂可能会在晚期 AD 患者的治疗中发挥作用。
The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (ACNE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer's disease (AD). While ACNE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase.In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and ACNE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors.The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use.The association between a BuChE-K variant and AD has not been confirmed in several studies.In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.