Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institute, Stockholm, Sweden.
Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institute, Stockholm, Sweden Faculty of Psychology and Educational Sciences, Semnan University, Semnan, Iran.
J Alzheimers Dis. 2014;39(2):423-40. doi: 10.3233/JAD-130845.
Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.
尽管在阿尔茨海默病（AD）领域进行了长达三十年的深入研究，并且进行了许多新治疗药物的临床试验，但胆碱酯酶抑制剂（ChEIs）仍然是 AD 和路易体痴呆的主要治疗方法。ChEIs 的药效动力学分析提供了矛盾的观察结果。使用快速可逆的、非氨基甲酰化的 ChEIs（多奈哌齐、加兰他敏和他克林）治疗会增加乙酰胆碱酯酶（AChE）蛋白表达，而氨基甲酰化药物利斯的明则产生持续抑制，AChE 蛋白表达没有明显变化。尽管如此，所有这些药物的症状临床疗效都相似。我们在这里首次报告，另一种氨基甲酰化 ChEI 苯海索治疗可在 AD 患者的脑脊液（CSF）中产生持续但温和的 AChE 抑制作用。我们还表明，苯海索治疗可逆转多奈哌齐诱导的 AChE 表达升高。对另一更大患者队列接受多奈哌齐治疗的 CSF 的进一步分析表明，除了其主要作用模式外，多奈哌齐还产生了两种具有潜在矛盾结果的其他药效动力学。多奈哌齐诱导的 AChE 表达有利于 AChE 驱动的淀粉样蛋白-β肽（Aβ）聚集，而多奈哌齐本身则以浓度依赖的方式拮抗 AChE 诱导的 Aβ聚集，这很可能是通过与 AChE 蛋白上的外周阴离子部位竞争与 Aβ肽结合。同时给予氨基甲酰化剂苯海索可减少多奈哌齐治疗患者的 AChE 蛋白表达，这可能使多奈哌齐分子只能阻止 Aβ与 AChE 之间的相互作用。本研究表明，在长期接受多奈哌齐治疗的患者中，联合使用低剂量的氨基甲酰化剂的附加治疗策略，应作为增强这些药物在痴呆疾病中的临床疗效的一种策略进行探索。
