The novel GLP-1 / GIP dual agonist DA3-CH is more effective than liraglutide in the MPTP mouse model of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease worldwide with a high incidence rate. The abnormality of the Wnt/β-catenin signaling pathway is closely related to the occurrence of Parkinson's disease (PD). Incretins can play a neuroprotective role in PD mouse models. We aimed to investigate whether the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) dual agonist DA3-CH and the GLP-1 mono-agonist liraglutide can exert a neuroprotective effect on PD model mice by activating the Wnt/β-catenin signaling pathway. Forty male C57BL/6 mice were randomly assigned to the following groups. (A) Control group: treated with saline; (B)MPTP group: 4 intraperitoneal MPTP injections on day 1 (25 mg/kg/2h,i.p.) + saline (0.1 ml i.p) for 6 days starting the day after day 1; (C) liraglutide group: 4 intraperitoneal MPTP injections on day 1(25 mg/kg/2h,i.p.) + liraglutide (25 nmol/kg/day i.p.) for 6 days after day 1; (D) DA3-CH group: 4 intraperitoneal MPTP injections on day 1 (25 mg/kg/2 h, i.p.) + DA3-CH (25 nmol/kg/day i.p.) for 6 days after day 1. Behavioral analysis and biomarker analysis were performed. The study showed that incretin mimetics can significantly reduce the decline in motor function of Parkinson's model mice, activate their Wnt/β-catenin signaling pathway, decrease the expression of α-Syn and GSK3β proteins, increase the expression of NeuN, β-catenin, Wnt3a and p-GSK3β proteins. The effect of the GLP-1/GIP dual receptor agonist DA3-CH is better than that of the GLP-1 single receptor agonist liraglutide. In terms of blood glucose and body weight, there was no difference between groups.