Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan province, China.
Basic Medical Collenge, Henan University of Chinese Medicine, Zhengzhou, Henan province, China.
J Parkinsons Dis. 2021;11(2):529-543. doi: 10.3233/JPD-202318.
Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer's disease related memory impairments. Parkinson's disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively.
The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model.
In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for 14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group.
The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH.
The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model.
胰高血糖素样肽 2（GLP-2）是一种肽类激素，来源于前胰高血糖素原基因，在肠道、胰腺和大脑中表达。一些先前的研究表明，GLP-2 改善了与衰老和阿尔茨海默病相关的记忆障碍。帕金森病（PD）是一种进行性神经退行性疾病，迄今为止，尚无特别有效的药物能有效逆转 PD 症状。
本研究旨在评估 GLP-2 类似物在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中的神经保护作用。
在本研究中，通过行为评估、透射电子显微镜、免疫荧光组织化学、酶联免疫吸附试验和 Western blot 检测，用蛋白酶抗性甘氨酰-GLP-2（50nmol/kg ip.）类似物在急性 PD 小鼠模型中进行了 14 天的测试。为了进行比较，用肠促胰岛素受体双重激动剂 DA5-CH 进行了另一个组的测试。
GLP-2 类似物治疗改善了小鼠的运动和探索活动，改善了小鼠的运动迟缓症和运动失衡。Gly（2）-GLP-2 治疗还保护多巴胺能神经元，并恢复黑质中酪氨酸羟化酶的表达水平。Gly（2）-GLP-2 还降低了小胶质细胞的激活程度，从而降低了 NLRP3 和白细胞介素-1β等促炎细胞因子的表达水平。此外，GLP-2 类似物改善了 MPTP 诱导的黑质中线粒体功能障碍。这些保护作用与双重激动剂 DA5-CH 相当。
本研究结果表明，Gly（2）-GLP-2 可以减轻 MPTP 诱导的黑质中 NLRP3 炎性小体介导的炎症和线粒体损伤，并且在这种 PD 动物模型中，Gly（2）-GLP-2 表现出神经保护作用。
