中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (8): 1660-1670.doi: 10.4103/1673-5374.303045

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

促胰岛素多肽双受体激动剂DA-CH5对帕金森病大鼠神经元的神经保护作用优于exendin-4

  

  • 出版日期:2021-08-15 发布日期:2021-01-14
  • 基金资助:

    山西省博士启动基金(SD1817

Glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide dual receptor agonist DA-CH5 is superior to exendin-4 in protecting neurons in the 6-hydroxydopamine rat Parkinson model

Ling-Yu Zhang1, Qian-Qian Jin2, Christian Hölscher3, 4, Lin Li1, *   

  1. 1Gerontology Institute, Shanxi Medical University, Taiyuan, Shanxi Province, China; 2Department of Forensic Pathology, Shanxi Medical University, Taiyuan, Shanxi Province, China; 3Department of Neurology, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi Province, China; 4Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
  • Online:2021-08-15 Published:2021-01-14
  • Contact: Lin Li, PhD, linlilin999@163.com.
  • Supported by:
    The study was supported by the Doctoral Start-Up Foundation of Shanxi Province of China, No. SD1817 (to QQJ).

摘要:

帕金森病患者大脑中胰岛素信号出现损伤,而胰高血糖素样肽1和葡萄糖依赖性促胰岛素多肽等肠促胰岛素可使胰岛素信号重新敏感。作者团队既往研究已通过在C末端添加TAT序列制备了一种新型胰高血糖素样肽1/葡萄糖依赖性促胰岛素多肽受体单分子共激动剂DA-CH5,其可穿越血脑屏障。但其对帕金森病是否存在神经保护作用尚不明确。(1)实验首先在对6-羟多巴胺诱导24h致损的SH-SY5Y细胞以100 nM DA-CH5干预,发现DA-CH5可通过激活胰岛素受体底物1/Akt/CREB通路;(2)在对右内侧前脑束定向注射6-羟多巴胺建立的帕金森病大鼠模型腹腔注射10 nmol/kg的DA-CH5进行检测时发现,大鼠运动功能障碍明显减轻,且黑质中多巴胺能神经元缺失减少,且逆转黑质中凋亡相关蛋白的表达,抑制胶质纤维酸性蛋白、线粒体应激蛋白(过氧化物酶体增殖激活受体辅助活化因子1α和核呼吸因子1)、α-突触核蛋白和促炎性细胞因子表达,上调自噬相关蛋白Beclin-1和SQSTM1的表达,抑制胰岛素拮抗相关蛋白胰岛素受体底物1磷酸化以及过氧化物酶体增殖激活受体辅助活化因子1α和核呼吸因子1的表达;且DA-CH5的上述神经保护作用优于已经II期临床试验验证的胰高血糖素样肽1模拟物exendin-4;(3)结果表明DA-CH5可通过减弱神经炎症,维持黑质多巴胺水平以及多巴胺能神经元数量,对6-羟多巴胺诱导的帕金森病大鼠模型有治疗作用,且效果优于exendin-4。实验经山西医科大学动物伦理委员会批准。

https://orcid.org/0000-0002-3121-2984 (Ling-Yu Zhang)

关键词: 神经退行性疾病, 帕金森病, 胰岛素拮抗, 炎症, 自噬, 神经元, 修复, 保护

Abstract: Patients with Parkinson’s disease (PD) have impaired insulin signaling in the brain. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), can re-sensitize insulin signaling. In a recent phase II clinical trial, the first GLP-1 mimic, exendin-4, has shown reliable curative effect in patients with PD. DA-CH5 is a novel GLP-1/GIP receptor unimolecular co-agonist with a novel peptide sequence added to cross the blood-brain barrier. Here we showed that both exendin-4 and DA-CH5 protected against 6-hydroxydopamine (6-OHDA) cytotoxicity, inhibited apoptosis, improved mitogenesis and induced autophagy flux in SH-SY5Y cells via activation of the insulin receptor substrate-1 (IRS-1)/alpha serine/threonine-protein kinase (Akt)/cAMP response element-binding protein (CREB) pathway. We also found that DA-CH5 (10 nmol/kg) daily intraperitoneal administration for 30 days post-lesion alleviated motor dysfunction in rats and prevented stereotactic unilateral administration of 6-OHDA induced dopaminergic neurons loss in the substantia nigra pars compacta. However, DA-CH5 showed curative effects in reducing the levels of α-synuclein and the levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β). It was also more effective than exendin-4 in inhibiting apoptotic process and protecting mitochondrial functions. In addition, insulin resistance was largely alleviated and the expression of autophagy-related proteins was up-regulated in PD model rats after DA-CH5 treatment. These results in this study indicate DA-CH5 plays a therapeutic role in the 6-OHDA-unilaterally lesioned PD rat model and is superior to GLP-1 analogue exendin-4. The study was approved by the Animal Ethics Committee of Shanxi Medical University of China.

Key words: neurodegenerative disease, Parkinson’s disease, insulin resistance, inflammation, GLP-1/GIP receptor unimolecular co-agonist