A GLP-1/apelin dual receptor agonist shows neuroprotective effects in the MPTP mouse model of Parkinson's disease

Parkinson's disease (PD) is a chronic disorder with no disease-modifying treatment available. The glucagon-like peptide-1 (GLP-1) class of drugs is on the market to treat diabetes and obesity. GLP-1 drugs have also shown neuroprotective effects in animal models and clinical trials in PD patients. Apelin (APJ) is an adipokine peptide hormone with neuroprotective actions in preclinical studies. Here, we test the effects of a rationally designed bifunctional peptide, namely ELA (exendin-4-linker-apelin), in the MPTP mouse model of PD. The single GLP-1 receptor agonist liraglutide was used as a comparator. Motor activity was improved by both drugs (open field, pole test, Rotarod), and the inflammation response was reduced (activation of microglia and astrocytes, pro-inflammatory cytokine levels). In addition, synapse numbers were improved in the striatum (Golgi strain, TEM), expression of synapse-associated proteins was enhanced, alongside reduced expression of genes that increase mitochondrial fission. Mitochondrial fusion gene expressions (Opa1, Mfn2, Drp1) and mitochondrial morphology were also normalized (TEM). ELA was superior to liraglutide in some, but not all, parameters measured. The results suggest that the rational design of bifunctional peptides targeting both GLP-1 and APJ pathways-with optimized pharmacokinetics and enhanced blood-brain barrier (BBB) permeability-merits further investigation as a strategy for developing more effective treatments for PD.