title: A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease.
abstract: The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects 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. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD.
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
authors.forename: Jaishree
authors.initials: J
authors.lastname: Jalewa
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Sharma
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Gengler
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk.
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D000071186:Beclin-1 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000978:Antiparkinson Agents; D000071186:Beclin-1; C512829:Becn1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000067757:Glucagon-Like Peptide-1 Receptor; D018696:Neuroprotective Agents; D011964:Receptors, Gastrointestinal Hormone; D016627:Oxidopamine; C041086:gastric inhibitory polypeptide receptor; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Brain; Incretin; Insulin; Neurodegeneration; Neuron; Neuroprotection