Francis P T, Palmer A M, Snape M, Wilcock G K
Dementia Research Laboratory, Neuroscience Research Centre, Guy's, King's and St Thomas' Schools of Biomedical Sciences, King's College, London, UK.
J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47. doi: 10.1136/jnnp.66.2.137.
Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
阿尔茨海默病是老年人精神衰退最常见的病因之一，约占65岁以上人群痴呆症病例总数的50%-60%。在过去二十年里，人们为发现阿尔茨海默病的病因付出了巨大的研究努力，最终希望研发出安全有效的药物治疗方法。本文通过描述阿尔茨海默病患者死后及神经外科脑活检时大脑中神经递质标志物的生化和组织病理学变化，以及拟胆碱药物和胆碱能损伤的行为后果，来探讨阿尔茨海默病原胆碱能假说现有的科学适用性。此类研究发现学习和记忆能力下降与兴奋性氨基酸（EAA）神经传递缺陷之间存在关联，同时胆碱能系统在注意力加工中以及作为EAA神经传递的调节剂发挥着重要作用。因此，尽管目前尚无治愈阿尔茨海默病的方法，但已出现大量旨在纠正突触前胆碱能功能丧失的潜在治疗干预措施。其中一些化合物已证实可有效延缓阿尔茨海默病症状的恶化，鉴于该疾病的渐进性，这是一个有价值的治疗目标。事实上，有三种化合物已获得欧洲批准用于治疗阿尔茨海默病的认知症状，第一种是他克林，最近的是多奈哌齐和卡巴拉汀，它们都是胆碱酯酶抑制剂。
