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摘要
阿尔茨海默病(AD)是一种进行性神经退行性疾病,其特点是总有β-淀粉样斑块和神经原纤维缠结。目前经批准的药物治疗方案只提供边际疗效,目前还没有有效的治疗方法来逆转或阻止疾病。迄今为止,靶向任何单一方面的疾病病理的药物已被证明失败或顶多带来非常少量的的临床益处。靶向β-淀粉样蛋白级联方面的的药物的持续的失败已质疑这条途径的因果作用。有越来越多的理解到该病的发病机制是多因素的β淀粉样蛋白、磷酸化的Tau蛋白(ptau)、炎症、线粒体功能障碍、钙稳态失衡、重金属失衡和GSK-3以高度复杂的方式相互作用,激发自我持续的呈螺旋式的病理级联效应,推动疾病的进展。由于如此复杂的病理学,靶向单一分子的药物的失败是不出人意料的,因为这样的方法通常对其他多因素的发病机制的复杂的疾病是无效的。联合疗法或多靶点药物可能更有效地控制此类疾病。通过大量的积极的自我平衡机制来实现锂公认的神经保护作用,即调节自我吞噬,氧化应激、炎症与可能通过抑制GSK-3和三磷酸肌醇-145而获得的线粒体功能障碍。关于AD的人体试验的功效和动物模型的资料已被混合,而最近用“微量”锂治疗轻度认知功能障碍的数据是令人振奋的,因此锂可以被推定是对此类患者的多靶点治疗。然而,考虑到有必要长期的使用以达到合理的治疗效果,需要附加精心设计的长期的临床试验,以确认其有效性和安全性,
关键词: 阿尔茨海默病,β-淀粉样蛋白,tau,钙,痴呆,炎症,铁,锂,小胶质细胞,线粒体,氧化应激,磷酸化
Current Alzheimer Research
Title:The Putative Use of Lithium in Alzheimer’s Disease
Volume: 13 Issue: 8
Author(s): Gerwyn Morris and Michael Berk
Affiliation:
关键词: 阿尔茨海默病,β-淀粉样蛋白,tau,钙,痴呆,炎症,铁,锂,小胶质细胞,线粒体,氧化应激,磷酸化
摘要: Alzheimer's disease is a progressive neurodegenerative illness characterized by the invariant existence of β-amyloid plaques and neurofibrillary tangles. Presently approved pharmaceutical approaches offer only marginal efficacy and as yet there is no effective treatment which reverses or arrests the disease. Thus far, drugs targeting any single aspect of disease pathology have proved to be a failure or at best provided very slight clinical benefit. The consistent failure of drugs targeting aspects of the Aβ cascade has questioned the causal role of this pathway. There is a growing appreciation that the pathogenesis of the illness is multifactorial with Amyloid Beta, Phosphorylated Tau (ptau), inflammation, mitochondrial dysfunction, calcium dyshomeostasis, heavy metal imbalances, and GSK-3 interact in a highly complex manner to provoke a selfsustaining spiraling cascade of pathology, driving disease progression. In the light of such complex pathology, the failure of drugs aimed a targeting single molecules is not surprising as such approaches are usually ineffective against other complex diseases with a multifactorial pathogenesis. Combination therapies or multi target drugs might be more effective in controlling such illnesses. The putative neuroprotective effects of Lithium are achieved via the positive modulation of numerous homeostatic mechanisms regulating autophagy, oxidative stress, inflammation, and mitochondrial dysfunction likely achieved by inhibiting GSK-3 and inositol-145 triphosphate. Data regarding efficacy in human trials and animal models of AD are mixed, but recent data using “microdose” lithium in mild cognitive impairment is encouraging, hence lithium could be a putative multi target treatment in these patients. However, additional well designed long-term trials are needed to confirm its efficacy and safety, given that long term use is necessary to achieve reasonable therapeutic benefit.
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Cite this article as:
Gerwyn Morris and Michael Berk , The Putative Use of Lithium in Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (8) . https://dx.doi.org/10.2174/1567205013666160219113112
DOI https://dx.doi.org/10.2174/1567205013666160219113112 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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