Zhou Zhi Dong, Yi Lingxiao, Popławska-Domaszewicz Karolina, Chaudhuri Kallol Ray, Jankovic Joseph, Tan Eng King
National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore.
Pharmacol Res. 2025 Jun;216:107770. doi: 10.1016/j.phrs.2025.107770. Epub 2025 May 8.
Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.
胰高血糖素样肽-1（GLP-1）受体激动剂（GRA）属于一类化合物，其通过模拟内源性肠促胰岛素激素GLP-1在进食后由肠道释放后的作用来降低血糖和能量摄入。它们用于治疗2型糖尿病（T2DM）和肥胖症，并且对包括脑、肝、胰腺、心脏和肠道在内的各种器官具有全身作用。T2DM患者发生神经退行性疾病（ND）的风险更高，包括阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）和亨廷顿病（HD），伴有更严重的运动缺陷和更快的疾病进展，这表明这些疾病中存在胰岛素信号传导失调。实验研究表明，GRA具有调节神经炎症、氧化应激、线粒体和自噬功能以及蛋白质错误折叠的保护作用。因此，这些化合物作为针对ND的新型治疗药物引起了极大的兴趣。迄今为止，临床试验表明，三种GRA，即艾塞那肽、利拉鲁肽和利司那肽，作为附加疗法可改善PD患者的运动缺陷，利拉鲁肽可改善AD患者的认知功能。这些以及其他GRA，如PT320（长效释放艾塞那肽）和司美格鲁肽的神经保护作用仍在研究中。双重GLP-1/胃抑制多肽（GIP）受体激动剂已被证明在AD和PD小鼠模型中具有有益作用。总体而言，GRA是非常有前景的新型药物，但未来的临床研究应确定哪些患者亚组应作为其症状性和/或神经保护益处的潜在候选者，研究与其他类药物联合使用是否能进一步提高其疗效，并评估其长期疾病修饰作用和不良反应。
