“老药新用”? 一糖尿病药物有望逆转老年痴呆
2018/01/03
2017年末,一篇发表在《Brain Research》期刊的文章揭示,一种治疗糖尿病的药物或许能应用于阿尔兹海默症领域。科学家们发现,它能够“显著逆转痴呆小鼠的学习、记忆衰退病症”。


One in three people will be diagnosed with Alzheimer's. (图片来源: Lancaster University

这一研究由来自于英国兰卡斯特大学、中国山西医科大学、邵阳学院的研究团队完成,证实一种2型糖尿病治疗药物能够给阿尔兹海默症带来实质性改善。

团队负责人、英国兰卡斯特大学首席研究员Christian Holscher教授认为,这一“老用新药”的研究思路有望为神经衰退性疾病提供新的选择。

2型糖尿病与阿尔兹海默症有相关性

2型糖尿病是引发阿尔兹海默症的危险因素之一。已有研究表明,胰岛素不足与神经退化有关联。而且,在老年痴呆患者大脑中发现了胰岛素脱敏现象,有专家推测脱敏在神经性障碍发展过程中发挥一定作用,因为胰岛素对于神经系统具有保护作用。

“近15年来,对于阿尔兹海默症我们一直未能研发出新的治疗方法。现在,这一研究方法有望更快地给患者带来有效的治疗药物。” 阿尔兹海默症协会研究和发展主任Doug Brown博士如此评价道。


视频来源:Lancaster University

3重受体激动剂有神经保护效应

在这一研究中,科学家们关注的是一款治疗2型糖尿病的新型的“3重受体激动剂”(a triple receptor agonist,TA)——同时靶向胰高血糖素样肽-1(GLP-1)、糖依赖性胰岛素释放肽(GIP)和胰高血糖素(Glucagon)3个受体。在阿尔兹海默症患者的大脑中,这些生长因子信号被证实存在缺陷。

研究团队以转基因小鼠(携带人阿尔兹海默症突变基因)为模型,每日注射糖尿病药物。持续2个月后,通过迷宫测试发现该药物能够显著改善小鼠的学习和记忆能力,具体表现为:1)上调大脑中保护神经细胞功能的生长因子水平;2)减少淀粉样蛋白病斑的数量;3)缓解慢性炎症和氧化应激;4)降低神经细胞的损伤速度。

总而言之,这种新型的三重受体激动剂表现出一定的神经保护效应。虽然目前关于“三重激动剂”对于神经类疾病的研究只局限于动物模型,但是其他针对现有糖尿病药物的研究已经显示出治疗阿尔兹海默症的潜在效果。所以,科学家们依然对此持乐观态度,未来还将在用药剂量以及对比其他现有药物方面投入大量研究。

参考资料:

Diabetes drug 'significantly reverses memory loss' in mice with Alzheimer's

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  • Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease

    Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10 nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD.

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