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

Abstract

Abstract 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.

Keywords

• apoptosis
• autophagy
• BBB
• growth factor
• insulin
• oxidative stress