Hölscher Christian
Biomedical and Life Sciences, Lancaster University, Lancaster LA1 4YQ, UK.
Sheng Li Xue Bao. 2014 Oct 25;66(5):497-510.
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.
2型糖尿病已被确定为阿尔茨海默病（AD）和帕金森病（PD）的一个风险因素。在AD和PD患者的大脑中，胰岛素信号传导受损。这一发现推动了新的研究，结果表明，最初用于治疗糖尿病的药物产生了良好效果。临床前研究表明，应用胰岛素或长效肠促胰岛素类似物具有良好的神经保护作用。在AD或PD的转基因动物模型中，肠促胰岛素胰高血糖素样肽-1（GLP-1）的类似物可预防神经退行性病变，改善神经元和突触功能，并减轻疾病症状。在转基因AD小鼠模型中，淀粉样斑块负荷、突触丧失以及认知障碍均得到了预防，而在PD动物模型中，多巴胺能传递丧失和运动功能也得到了逆转。基于这些有前景的发现，目前正在进行多项临床试验，并且已经发表了首批令人鼓舞的临床结果。在针对AD患者的多项试点研究中，经鼻应用胰岛素对认知和生物标志物显示出了令人鼓舞的效果。一项针对PD患者的试点研究测试了一种目前作为2型糖尿病治疗药物上市的GLP-1受体激动剂（艾塞那肽，百泌达），结果也显示出了令人鼓舞的效果。目前，针对AD患者正在进行其他多项临床试验，测试另一种已上市的GLP-1类似物（利拉鲁肽，维达列汀）。最近，第三种GLP-1受体激动剂已在欧洲上市（利司那肽，利时敏），其神经保护作用也非常有前景。本综述将总结这些药物已证明的一系列保护作用。GLP-1类似物有望提供新的治疗方法，这些方法可能对AD和PD具有保护甚至再生作用，而目前尚无药物能做到这一点。
