title: A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson's disease by increasing expression of BNDF.
abstract: The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. 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 and are tested in diabetic patients. Here we demonstrate 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 i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Ji
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Xue
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Cao
authors.initials: C
authors.lastname: Lijun
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Feng
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Li
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China. Electronic address: smuneu@163.com.
authors.forename: Guanglai
authors.initials: G
authors.lastname: Li
authors.affiliation: Second Hospital, Shanxi Medical University, Taiyuan, PR China; Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D045442:Rotarod Performance Test; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D011964:Receptors, Gastrointestinal Hormone; C041086:gastric inhibitory polypeptide receptor; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: AKT; Apoptosis; Growth factor; Incretin; Insulin; Neuron