title: Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease.
abstract: Oxyntomodulin is a hormone and a growth factor. It activates two receptors, the Glucagon-like peptide 1 (GLP-1) and the glucagon receptor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first positive results. D-Ser2-oxyntomodulin (Oxy) is a protease resistant oxyntomodulin analogue that has been developed to treat diabetes. Here we demonstrate for the first time that such analogues have neuroprotective effects. The drug showed protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected daily (20 mg/kg i.p.) for 7 days, and Oxy injected once-daily for 14 days i.p. Oxy treatment prevented or reversed the MPTP- induced motor impairment (Rotarod, spontaneous locomotion, swim activity, muscle strength test), the MPTP-induced reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, the reduction of the synaptic marker synapstophysin, the inactivation of the growth factor kinase Akt/PKB and of the anti-apoptotic signaling molecule Bcl-2, and the increase of levels of the pro-inflammatory cytokine TNF-α. The results demonstrate that oxyntomodulin analogues show promise as a novel treatment of PD.
authors: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors: WeiZhen
authors: W
authors: Liu
authors: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors: Yanwei
authors: Y
authors: Li
authors: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors: Jaishree
authors: J
authors: Jalewa
authors: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors: Taylor
authors: T
authors: Saunders-Wood
authors: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China. Electronic address: linlilin999@163.com.
authors: Lin
authors: L
authors: Li
authors: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors: Christian
authors: C
authors: Hölscher
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053772:Oxyntomodulin / Q000008:administration & dosage / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000473:pathology / Q000517:prevention & control*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D013550:Swimming; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C000609716:D-Ser2-oxyntomodulin; D018696:Neuroprotective Agents; D053772:Oxyntomodulin; D052216:Glucagon-Like Peptide 1; D014446:Tyrosine 3-Monooxygenase
keywords: GLP-1; Glucagon; Growth factor; Incretin; Insulin; Mice; Neurodegeneration