The novel GLP-1/GIP dual receptor agonist DA5-CH is superior to tirzepatide and exendin-4 in the 6-OHDA Parkinson rat model.

INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no cure. Diabetes is one of the risk factors for developing PD. Tirzepatide is a novel long-acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that is on the market as a treatment for diabetes. Importantly, two phase II trials in PD patients showed good effects with the GLP-1 receptor agonists Exendin-4 and Lixisenatide. METHODS: We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than Tirzepatide. Here, we tested Exendin-4, Tirzepatide and DA5-CH in the 6-OHDA-lesion rat model of PD. The drug treatment was daily (10 nmol/kg, ip.) for 30 days. RESULTS: DA5-CH was more effective than Tirzepatide or Exendin-4. In the substantia nigra, dopaminergic neurons were protected, with DA5-CH being most effective. Dopamine levels in the striatum were normalized by DA5-CH, while Exendin-4 was less effective, and Tirzepatide was ineffective. The inflammation response in the lesioned striatum was reduced by the drugs as shown in reduced IL-6 and TNF-α levels, with DA5-CH being more effective than Exendin-4, and Tirzepatide showing minimal effects. Furthermore, the α-synuclein levels in the substantia nigra were reduced by DA5-CH, superior to Exendin-4 and Tirzepatide. DISCUSSION: Therefore, DA5-CH was more effective and may be a better therapeutic drug for neurodegenerative disorders such as PD compared to Tirzepatide or Exendin-4.