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抗糖尿病药物有助于治疗阿尔茨海默病和帕金森病

Christian Hölscher^*

兰卡斯特大学生物医学和生命科学学院，兰卡斯特LA1 4YQ，英国

摘要

2型糖尿病已被证实是阿尔茨海默病(Alzheimer’s disease, AD)和帕金森病(Parkinson’s disease, PD)的一个危险因素。已有报道表明，AD和PD患者脑内的胰岛素信号转导受到损害。这一发现使抗糖尿病药物的应用有了新的研究，并显示出良好效应。临床前期试验表明，胰岛素或长效肠促胰岛素肽(incretin peptide)类似物具有良好的神经保护作用。在AD和PD转基因模型动物中，胰高血糖素样肽1 (GLP-1，一种肠促胰岛素的类似物)阻止了神经退行性变进程，改善了神经元和突触的功能，并减轻了疾病的症状。在AD转基因小鼠模型中，GLP-1类似物阻止了淀粉样斑块的沉积、突触的丧失以及认知功能的损害；在PD动物模型中，GLP-1类似物改善了多巴胺能神经传递和运动功能。在此基础上，临床试验也在进行之中，并显示出令人鼓舞的结果。在AD患者中的初步研究表明，鼻腔给予胰岛素可改善患者的认知功能并减少脑内的AD标志物。对PD患者的初步研究也表明，目前已经上市用于治疗2型糖尿病的一种GLP-1受体激动剂(exendin-4, Byetta)对PD病人具有良好的疗效。另一种上市用于治疗糖尿病的GLP-1类似物(liraglutide, Victoza)也正在AD患者中进行临床测试。最近，第三种GLP-1受体激动剂(Lixisenatide, Lyxumia)已经在欧洲被批准上市，该药物也显示了良好的神经保护作用。本文将就以上抗糖尿病药物的神经保护作用进行归纳。可见，GLP-1类似物所显示的神经保护乃至神经再生作用为AD和PD提供了一种新的治疗手段，这些作用是当前其它药物所不具备的。

关键词： 糖尿病; 记忆; 帕金森病; 神经退行性变; 神经生长因子; 胰岛素; 阿尔茨海默病; 神经毒性

分类号：R335+.6;R338;R741

Drugs developed for treatment of diabetes show protective effects in Alzheimer's and Parkinson's diseases

Christian Hölscher^*

Biomedical and Life Sciences, Lancaster University, Lancaster LA1 4YQ, UK

Abstract

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does.

Key words: Diabetes; memory; Parkinson’s disease; neurodegenerative; nerve growth factor; insulin; Alzheimer’s disease; neurotoxicity

收稿日期：2014-03-14　　录用日期：2014-04-17

通讯作者：Christian Hölscher　　E-mail: c.holscher@lancaster.ac.uk

引用本文：

Christian Hölscher. 抗糖尿病药物有助于治疗阿尔茨海默病和帕金森病[J]. 生理学报 2014; 66 (5): 497-510.

Christian Hölscher. Drugs developed for treatment of diabetes show protective effects in Alzheimer's and Parkinson's diseases. Acta Physiol Sin 2014; 66 (5): 497-510 (in Chinese with English abstract).