Lingyu Zhang1, Liping Zhang1, Yanwei Li2, Lin Li1, Josefine Ulrikke Melchiorsen3, Mette Rosenkilde3, Christian Hölscher4,5. 1. Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. 2. Department of Human Anatomy, Shaoyang Medical College, Shaoyang, Hunan, PR China. 3. Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark. 4. Department of Second Hospital Neurology, Shanxi Medical University, Taiyuan, Shanxi, PR China. 5. Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan province, PR China.
Abstract
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.
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 PDpatients. 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 MPTPmouse 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.
Authors: Richard A Manfready; Phillip A Engen; Leo Verhagen Metman; Gabriella Sanzo; Christopher G Goetz; Deborah A Hall; Christopher B Forsyth; Shohreh Raeisi; Robin M Voigt; Ali Keshavarzian Journal: Front Neurosci Date: 2021-07-02 Impact factor: 4.677
Authors: Mara Dierssen; Marta Fructuoso; María Martínez de Lagrán; Marzia Perluigi; Eugenio Barone Journal: Front Neurosci Date: 2020-07-08 Impact factor: 4.677