In an acute MPTP mouse model, a GLP-2 analogue and a GLP-2/GIP dual agonist improved motor performance and reduced α‑synuclein accumulation, neuroinflammation (TNF‑α, NF‑κB) and apoptosis (↓Bax, ↑Bcl‑2), with the dual agonist showing superior effects.

Provides preclinical evidence that GLP-2/GIP receptor co-agonism can modulate key PD-relevant mechanisms (inflammation, α‑synuclein, apoptosis), supporting further translational work (chronic models, mechanism dissection, PK/safety) toward a potential disease-modifying therapy.

BACKGROUND: Neuroinflammation and apoptosis constitute central pathological processes in the progression of Parkinson's disease (PD). Glucagon-like peptide-2 (GLP-2) has shown promise as a neuroprotective agent in neurodegenerative disorders, as has Glucose-dependent insulinotropic polypeptide (GIP). OBJECTIVE: This study aimed to evaluate the neuroprotective effects of a GLP-2 analogue and a GLP-2/GIP dual receptor agonist in an MPTP-induced mouse model of PD, to see if the addition of the GIP binding site improves neuroprotection. METHODS: C57BL/6 mice were randomly divided into four groups: saline control group, MPTP saline group, MPTP +GLP-2 receptor agonist treatment group, and MPTP GLP-2/GIP dual agonist treatment. An acute PD model was established by intraperitoneal injection of MPTP. Motor function was assessed using open field test and gait analysis. Protein expression levels of α-synuclein (α-syn), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), Bax, and Bcl-2 in the substantia nigra were detected by western blot and immunohistochemistry. RESULTS: Compared with the control group, motor function was significantly improved in both the GLP-2 analogue and GLP-2/GIP dual agonist groups. At the molecular level, both treatments significantly reduced the expression of the pro-inflammatory factors TNF-α and NF-κB, as well as the pro-apoptotic protein Bax, while upregulating the expression of the anti-apoptotic protein Bcl-2 and reducing the abnormal accumulation of α-syn. The dual agonist group demonstrated superior efficacy in all parameters, suggesting that it may exert enhanced neuroprotective effects through the activation of synergistic signaling pathways mediated by the GIP receptor. The dual GLP-2/GIP receptor agonist shows promise as a novel treatment for PD.