The Novel Dual GLP-1/GIP Receptor Agonist DA-CH5 Is Superior to Single GLP-1 Receptor Agonists in the MPTP Model of Parkinson's Disease
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The Novel Dual GLP-1/GIP Receptor Agonist DA-CH5 Is Superior to Single GLP-1 Receptor Agonists in the MPTP Model of Parkinson's Disease. / Zhang, Lingyu; Zhang, Liping; Li, Yanwei; Li, Lin; Melchiorsen, Josefine Ulrikke; Rosenkilde, Mette; Holscher, Christian.
In: Journal of Parkinson's Disease, Vol. 10, No. 2, 2020, p. 523-542.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Novel Dual GLP-1/GIP Receptor Agonist DA-CH5 Is Superior to Single GLP-1 Receptor Agonists in the MPTP Model of Parkinson's Disease
AU - Zhang, Lingyu
AU - Zhang, Liping
AU - Li, Yanwei
AU - Li, Lin
AU - Melchiorsen, Josefine Ulrikke
AU - Rosenkilde, Mette
AU - Holscher, Christian
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Dopamine
KW - growth factors
KW - insulin
KW - mitochondria
KW - neuroprotection
KW - neuron
KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE
KW - GLUCAGON-LIKE PEPTIDE-1
KW - MOUSE MODEL
KW - OXIDATIVE STRESS
KW - 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP
KW - CHRONIC INFLAMMATION
KW - UP-REGULATION
KW - CELL-DEATH
KW - LIRAGLUTIDE
KW - ALZHEIMERS
U2 - 10.3233/JPD-191768
DO - 10.3233/JPD-191768
M3 - Journal article
C2 - 31958096
VL - 10
SP - 523
EP - 542
JO - Journal of Parkinson's Disease
JF - Journal of Parkinson's Disease
SN - 1877-7171
IS - 2
ER -
ID: 246871872