title: Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
abstract: Glucagon-like peptide 1 (GLP-1) is a growth factor. 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 results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD.
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Jalewa
authors.affiliation: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second Hospital, Shanxi Medical University, Taiyuan, PR China. Electronic address: c.holscher@lancaster.ac.uk.
authors.forename: C
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D000077270:Exenatide; D000069450:Liraglutide / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000503:physiopathology / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage*; D045442:Rotarod Performance Test; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077270:Exenatide; D000069450:Liraglutide; D018696:Neuroprotective Agents; D010455:Peptides; D014446:Tyrosine 3-Monooxygenase; D014688:Venoms; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: apoptosis; basal ganglia; growth factor; incretin; insulin; neurodegeneration