title: A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson's disease by reducing chronic inflammation in the brain.
abstract: The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.
authors.affiliation: aDepartment of Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster, UK bDepartment of Neurology, The Second Affiliated Hospital of Shanxi Medical University cKey Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Cao
authors.forename: Dongfang
authors.initials: D
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Feng
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Xue
authors.forename: Guanglai
authors.initials: G
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D010455:Peptides / Q000627:therapeutic use*; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D000978:Antiparkinson Agents; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D014446:Tyrosine 3-Monooxygenase; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C491049:Aif1 protein, mouse; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C041086:gastric inhibitory polypeptide receptor