Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells

J Neurochem. 2016 Oct;139(1):55-67. doi: 10.1111/jnc.13736. Epub 2016 Aug 24.

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.

Keywords: Parkinson's disease; autophagy; growth factors; incretins; oxidative stress; rotenone.

MeSH terms

  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Cell Line
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Electron Transport Complex I / antagonists & inhibitors
  • Glucagon-Like Peptide 1 / antagonists & inhibitors
  • Humans
  • Incretins / chemistry
  • Incretins / pharmacology*
  • Mitochondria / drug effects*
  • Morpholines / pharmacology
  • Neuroprotective Agents / pharmacology*
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • Oxidative Stress / drug effects
  • Phosphoinositide-3 Kinase Inhibitors
  • Rotenone / antagonists & inhibitors*
  • Rotenone / pharmacology*
  • Stress, Physiological / drug effects*
  • Uncoupling Agents / pharmacology*

Substances

  • Chromones
  • Incretins
  • Morpholines
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Uncoupling Agents
  • Rotenone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Glucagon-Like Peptide 1
  • Oncogene Protein v-akt
  • Electron Transport Complex I