利拉鲁肽
兴奋剂
内分泌学
内科学
受体
胰高血糖素样肽1受体
医学
内源性激动剂
化学
药理学
多巴胺受体D1
糖尿病
2型糖尿病
作者
Lingyu Zhang,Ping Zhang,Wei Wang,Lin Li,Josefine Ulrikke Melchiorsen,Mette M. Rosenkilde,Christian Hölscher
出处
期刊:Journal of Parkinson's disease
[IOS Press]
日期:2020-04-03
卷期号:10 (2): 523-542
被引量:53
摘要
Background:Parkinson's disease (PD) is a progressive neurodegenerative disease for which there is no cure. In a clinical trial, the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has shown good protective effects in PD patients. The hormone glucose-dependent insulinotropic polypeptide ( GIP) has also shown protective effects in animal models of PD. Objective:We tested DA-CH5, a novel dual GLP-1/GIP receptor agonist. Methods:DA-CH5 activity was tested on cells expressing GLP-1, GLP-2, GIP or glucagon receptors. The ability to cross the blood-brain barrier (BBB) of DA-CH5, exendin-4, liraglutide or other dual receptor agonists was tested with fluorescein-labelled peptides. DA-CH5, exendin-4 and liraglutide were tested in the MPTP mouse model of PD. Results:Analysing the receptor activating properties showed a balanced activation of GLP-1 and GIP receptors while not activating GLP-2 or glucagon receptors. DA-CH5 crossed the BBB better than other single or other dual receptor agonists. In a dose-response comparison, DA-CH5 was more effective than the GLP-1 receptor agonist exendin-4. When comparing the neuroprotective effect of DA-CH5 with Liraglutide, a GLP-1 analogue, both DA-CH5 and Liraglutide improved MPTP-induced motor impairments. In addition, the drugs reversed the decrease of the number of neurons expressing tyrosine hydroxylase (TH) in the SN, alleviated chronic inflammation, reduced lipid peroxidation, inhibited the apoptosis pathway (TUNEL assay) and increased autophagy -related proteins expression in the substantia nigra (SN) and striatum. Importantly, we found DA-CH5 was superior to Liraglutide in reducing microglia and astrocyte activation, improving mitochondrial activity by reducing the Bax/Bcl-2 ratio and normalising autophagy as found in abnormal expression of LC3 and p62. Conclusion:The results demonstrate that the DA-CH5 is superior to liraglutide and could be a therapeutic treatment for PD.
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