title: Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells.
abstract: Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 μM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 μM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells treated with the stressor Rotenone. The novel GLP-1/GIP dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. The drugs protected the cells from rotenone-induced impairment in cell growth and Akt activation, mitochondrial damage, impairments of autophagy and apoptotic cell signalling. See paper for details.
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. c.holscher@lancaster.ac.uk.
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors; D006801:Humans; D054795:Incretins / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012402:Rotenone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D002867:Chromones; D054795:Incretins; D009025:Morpholines; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014475:Uncoupling Agents; D012402:Rotenone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052216:Glucagon-Like Peptide 1; D051058:Oncogene Protein v-akt; D042967:Electron Transport Complex I
keywords: Parkinson's disease; autophagy; growth factors; incretins; oxidative stress; rotenone