胰高血糖素样肽1受体激动剂在神经保护方面的研究进展

Research advances in the neuroprotective effect of glucagon-like peptide-1 receptor agonists

近年来的研究发现,与糖尿病并发的多种神经系统疾病,可随着治疗糖尿病的胰高血糖素样肽1受体激动剂(GLP-1RA)的使用而得到改善,但其具体机制尚不完全清楚。天然的GLP-1是进食诱导刺激回肠和结肠的L细胞分泌的肠肽类激素,其可促进胰岛素的合成和分泌。为克服GLP-1半衰期短而开发的多种长效GLP-1RA已经在临床上广泛应用,如艾塞那肽、利拉鲁肽、阿必鲁肽、度拉糖肽等,这些药物表现出在控制血糖水平和体重上的优势。由于GLP-1受体广泛分布于胰腺、肺、脑、心脏、肾和胃肠等组织细胞膜上,因此GLP-1RA的作用不仅仅在治疗糖尿病方面。已有的报道表明,GLP-1RA还具有显著的神经、心血管、肾脏保护,以及抗呼吸道炎症和减脂等多种作用。GLP-1受体在脑中亦有广泛分布,且GLP-1RA可有效通过脑血管屏障。GLP-1RA与相应受体结合,可激活PKA、PI3K/AKT、ERK、MEK等多个激酶信号通路,调节神经递质传递,这可能是GLP-1RA实现抗炎、减少氧化应激、抑制凋亡、减少DNA损伤、神经细胞修复,最终达到神经保护的途径。该文结合基础及临床研究,对GLP-1RA在缺血性脑卒中、认知功能障碍、帕金森病等多种神经系统疾病中神经保护方面的研究进展进行综述,以期总结其作用机制,并讨论其作为神经保护药物的可能性。

Recent studies have found that various nervous system diseases in diabetes can be improved with the use of glucagon-like peptide-1 receptor agonists(GLP-1RA)for the treatment of diabetes,but its specific mechanism remains unclear.Natural glucagon-like peptide-1(GLP-1)is an intestinal peptide-like hormone secreted by feeding-induced stimulation of L cells in the ileum and colon and can promote insulin synthesis and secretion.A variety of long-acting GLP-1RA developed to overcome the short half-life of GLP-1 have been widely used in clinical practice,such as exenatide,liraglutide,albiglutide,and dulaglutide,which have shown advantages in controlling blood glucose level and body weight.Since of GLP-1 receptors are widely distributed on the cell membranes of tissues such as the pancreas,lung,brain,heart,kidney,and gastrointestinal tract,GLP-1RA may also exert a therapeutic effect on diseases other than diabetes.Existing reports have shown that GLP-1RA has a significant protective effect against neurological,cardiovascular,and renal diseases,and it can also help to alleviate respiratory inflammation and reduce body fat.GLP-1 receptors are also widely distributed in the brain,and GLP-1RA can effectively cross the blood-brain barrier.GLP-1RA binds to corresponding receptors to activate various kinase signaling pathways including PKA,PI3K/AKT,ERK,and MEK and regulate neurotransmitter transmission,which might be the pathway for GLP-1RA to exert a neuroprotective effect by alleviating inflammation,reducing oxidative stress,inhibiting apoptosis,reducing DNA damage,and repairing neural cells.With reference to related basic and clinical research,this article reviews the research advances in the neuroprotective effect of GLP-1RA in various nervous system diseases such as ischemic stroke,cognitive impairment,and Parkinson’s disease,so as to summarize its mechanism of action and explore its potential as a neuroprotective drug.