The GLP-1/GIP dual-receptor agonist DA5-CH inhibits the NF-κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP-1 single-receptor agonist NLY01.

The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor β1 (TGF-β1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iβ) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.