Lane Roger M, Potkin Steven G, Enz Albert
Novartis Neuroscience, Novartis Pharmaceuticals Corporation, NJ, USA.
Int J Neuropsychopharmacol. 2006 Feb;9(1):101-24. doi: 10.1017/S1461145705005833. Epub 2005 Aug 5.
The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.
胆碱酯酶抑制剂（ChE-Is）可减轻阿尔茨海默病（AD）患者认知和神经精神功能障碍背后的胆碱能缺陷。抑制脑乙酰胆碱酯酶（AChE）一直是治疗阿尔茨海默病（AD）的ChE-I治疗策略的主要治疗靶点。AChE阳性神经元广泛投射至皮质，调节皮质加工以及对新的相关刺激的反应。丁酰胆碱酯酶（BuChE）阳性神经元特异性投射至额叶皮质，可能在注意力、执行功能、情感记忆和行为方面发挥作用。此外，随着痴呆严重程度的进展，BuChE活性逐渐增加，而AChE活性下降。因此，抑制BuChE可能会带来额外益处。两种代谢乙酰胆碱（ACh）的胆碱酯酶（ChE）在底物特异性、酶动力学、在不同脑区的表达和活性以及基因调控的复杂性方面存在显著差异。此外，最近的证据表明，AChE和BuChE可能具有超越“经典”共同调节酯酶功能的作用，即在终止ACh介导的神经传递方面。在调节其他蛋白质的活性、局部脑血流、tau磷酸化和淀粉样蛋白级联反应方面的“非经典”作用可能会影响AD的进展速度。如果这些额外机制被证明是临床有意义效应的基础，那么修正AD中过于简单化的胆碱能假说可能是合适的，该假说仅限于对症治疗，而忽略了胆碱能疗法改变疾病进程的潜力。ChE抑制活性的特异性、AChE活性随时间的上调以及AChE分子形式组成的变化、对AD相关ChE分子形式的选择性、脑与外周的选择性以及药代动力学特征可能是不同ChE-Is急性和长期疗效、安全性和耐受性的重要决定因素。本综述重点关注BuChE和AChE在痴呆症状产生和潜在疾病进展速度方面作用的新证据，并认为重新评估ChE-Is在痴呆治疗中的地位可能是合适的。
