神经退行性疾病的治疗策略通常针对疾病发病机理的各个方面,但收效甚微。神经退行性疾病,包括阿尔茨海默病(AD)和帕金森病(PD),具有几种病理特征。在AD和PD中,有毒蛋白质的异常积累,炎症增加,突触功能下降,神经元丢失,星形胶质细胞激活增加,也许是胰岛素抵抗的状态。流行病学证据揭示了AD/PD与2型糖尿病之间的联系,这些疾病有一些共同的病理特征。这种联系为在神经退行性疾病的治疗中重新利用抗糖尿病药物开辟了有希望的途径。AD/PD的成功治疗策略可能需要靶向疾病中单独病理过程的单一或几种药剂。靶向脑胰岛素信号在临床前AD/PD脑模型中产生许多神经保护作用。临床试验表明,批准的糖尿病化合物有望改善PD的运动症状并预防神经退行性衰退,在AD和PD人群中正在进行许多进一步的II期试验和III期试验。除了胰岛素信号,靶向大脑中的肠降血糖素受体代表了用于重新利用目前可用的药物治疗AD/PD的最有希望的策略之一。最值得注意的是,胰高血糖素样肽-1(GLP-1)受体激动剂在临床前和早期临床研究中显示出令人印象深刻的临床潜力。在AD中,GLP-1受体激动剂,利拉鲁肽,在小规模的中试试验中已证明可以改善脑葡萄糖代谢和功能连接。在PD期间,GLP-1受体激动剂艾塞那肽可有效恢复运动功能和认知功能.靶向脑肠降血糖素受体减少炎症,抑制细胞凋亡,防止有毒蛋白质聚集,增强长期增强和自噬,并恢复功能失调的胰岛素信号。对使用其他批准的糖尿病治疗方法的支持也在增加,包括鼻内胰岛素,盐酸二甲双胍,过氧化物酶体增殖物激活核受体γ激动剂,胰淀素类似物,和蛋白酪氨酸磷酸酶1B抑制剂正在研究中用于PD和AD治疗。因此,我们对治疗AD和PD的几种有前景的抗糖尿病药物进行了全面综述.
Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer\'s disease (AD) and Parkinson\'s disease (PD), are characterized by several pathological features. In AD and PD, there is an abnormal accumulation of toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, increased astrocyte activation, and perhaps a state of insulin resistance. Epidemiological evidence has revealed a link between AD/PD and type 2 diabetes mellitus, with these disorders sharing some pathological commonalities. Such a link has opened up a promising avenue for repurposing antidiabetic agents in the treatment of neurodegenerative disorders. A successful therapeutic strategy for AD/PD would likely require a single or several agents which target the separate pathological processes in the disease. Targeting cerebral insulin signalling produces numerous neuroprotective effects in preclinical AD/PD brain models. Clinical trials have shown the promise of approved diabetic compounds in improving motor symptoms of PD and preventing neurodegenerative decline, with numerous further phase II trials and phase III trials underway in AD and PD populations. Alongside insulin signalling, targeting incretin receptors in the brain represents one of the most promising strategies for repurposing currently available agents for the treatment of AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists have displayed impressive clinical potential in preclinical and early clinical studies. In AD the GLP-1 receptor agonist, liraglutide, has been demonstrated to improve cerebral glucose metabolism and functional connectivity in small-scale pilot trials. Whilst in PD, the GLP-1 receptor agonist exenatide is effective in restoring motor function and cognition. Targeting brain incretin receptors reduces inflammation, inhibits apoptosis, prevents toxic protein aggregation, enhances long-term potentiation and autophagy as well as restores dysfunctional insulin signalling. Support is also increasing for the use of additional approved diabetic treatments, including intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear receptor γ agonists, amylin analogs, and protein tyrosine phosphatase 1B inhibitors which are in the investigation for deployment in PD and AD treatment. As such, we provide a comprehensive review of several promising anti-diabetic agents for the treatment of AD and PD.