Christian Holscher

Henan University of Chinese Medicine

Title: Novel dual GLP-1/GIP agonists are neuroprotective in Parkinson’s disease

Abstract: Type 2 diabetes mellitus (T2DM) is one of the risk factors for developing Parkinson’s disease (PD). The underlying mechanism appears to be the de-sensitisation of insulin signalling in the brain. On the basis of this, drugs that initially had been developed to treat diabetes have been tested. The group of Glucagon-like peptide-1 (GLP-1) receptor agonists have shown good protective effects. In a phase II trial, exendin-4 (Bydureon), a drug on the market to treat diabetes had been tested in PD patients. The drug stopped disease progression and patients showed improved motor performance compared to the placebo group, even three months after the drug treatment had stopped. This outcome is a proof of principle that GLP-1 receptor agonists have the potential to stop PD progression. We have tested a range of other GLP-1 mimetica including liraglutide, lixisenatide, and semaglutide, drugs that are currently on the market to treat T2DM. Several clinical trials are currently ongoing that are testing these drugs in PD patients. In addition, we tested protease resistent analogues of glucose-dependent insulinotropic polypeptide (GIP), the sister incretin hormone of GLP-1. GIP analogues were able to show good protective effects in PD animal models, too.
Recently, dual GLP-1/GIP receptor agonists have been developed to treat T2DM. Activating both receptors shows a synergistic effect. Several of these dual agonists have been tested in animal models of PD. Novel dual agonists that can penetrate the blood-brain barrier effectively have been developed and compared to other dual agonists that had been developed to treat T2DM. We showed superior neuroprotective effects of two novel dual agonists that can protect motor activity, dopaminergic neurons in the substantia nigra, reduce chronic inflammation in the brain, reduce -synuclein levels, normalise mitochondrial activity, reduce oxidative stress, re-sensitise insulin signalling, and normalise expression of key growth factors such as BDNF and GDNF. In conclusion, the novel dual GLP-1/GIP receptor agonists show great promise to be developed as an effective treatment for PD.