Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐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.

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

“…Furthermore, CREB can be activated and sustained by the CaMKII cascade (Ao, Ko, & Zhuo, ) and the activation of CREB by phosphorylation at Ser133 ( S133 p‐CREB) is critical for memory formation and LTP maintenance, because the downstream genes are involved in synaptic formation, neuronal plasticity and neurogenesis (Deisseroth et al, ). This study supports the conclusion above and provides a proof that the transcription factor CREB, part of this signaling pathway (Jalewa, Sharma, & Hölscher, ), was also re‐activated by the novel triagonist in the APP/PS1 AD mice. GSK‐3, a multifunctional kinase, phosphorylates the tau protein which aggregates to tangles in the AD brain (Perez‐Costas, Gandy, Melendez‐Ferro, Roberts, & Bijur, ).…”

A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model

“…Novel dual GLP-1/GIP receptor agonists have the advantage of activating two signaling pathways, and have been shown to be superior to single GLP-1 receptor agonists [31,61]. We previously reported that another dual agonists named DA-JC1 showed good neuroprotective effects in the MPTP mouse model of Parkinson's disease [33,62].…”

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

“…These dual receptor agonists show superior effects to single GLP-1 analogues such as liraglutide (Finan et al, 2013). We tested a novel dual agonist (DA-JC1) in rotenone stressed SH-SY5Y cells and demonstrated that it was cytoprotective at much lower doses than single GLP-1 or GIP receptor agonists (Jalewa et al, 2016). We furthermore tested DA-JC1 in the MPTP mouse model of PD, which showed some protective effect but which was not superior to liraglutide (Cao et al, 2016;Ji et al, 2016b).…”