Abstract
Objective: To further explore the mechanism of action of exenatide, a glucagon-like peptide-1 agonist, underlying the positive effects on motor function in a recently reported in a clinical trial of Parkinson’s disease.
Background: Exenatide, a glucagon-like peptide-1 agonist licensed for the treatment of Type 2 diabetes was recently found to have beneficial effects on motor function in a placebo-controlled trial in patients with moderate stage Parkinson’s disease (PD). Accumulating evidence suggests that impaired insulin and Akt signalling with consequent relative deactivation of cell survival pathways play a role in PD pathogenesis.
Design/Methods: We isolated serum extracellular vesicles (EVs) enriched for neuronal origin from trial participants and measuring concentrations of total and phosphorylated signalling proteins at various timepoints.
Neuronal insulin receptor mediated downstream signalling cascades were investigated by measuring levels of IRS-1 proteins, whereas evidence of potential Akt and MAPK pathway activation was determined by measurement of total and phosphorylated forms of key kinases Akt, mTOR, GSK-3B, p38, Erk1/2 and JNK.
Results: We found that, compared to placebo, peripherally administered exenatide can engage neuronal signalling pathways and promote activating phosphorylations on IRS-1 tyrosine residues and downstream substrates including Akt and mechanistic target of rapamycin (mTOR). Furthermore, the beneficial clinical effects of exenatide on motor function were associated with EV biomarker changes suggesting a reduction in neuronal insulin resistance and concomitant activation of mTOR signalling
Conclusions: The results suggest target engagement of insulin/Akt/mTOR signalling pathways in neurons by exenatide and provide a mechanistic context for the recent clinical findings of the trial.