The Novel Dual GLP-1/GIP Receptor Agonist DA-CH5 Is Superior to Single GLP-1 Receptor Agonists in the MPTP Model of Parkinson's Disease

J Parkinsons Dis. 2020;10(2):523-542. doi: 10.3233/JPD-191768.

Abstract

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease for which there is no cure. In a clinical trial, the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has shown good protective effects in PD patients. The hormone glucose-dependent insulinotropic polypeptide (GIP) has also shown protective effects in animal models of PD.

Objective: We tested DA-CH5, a novel dual GLP-1/GIP receptor agonist.

Methods: DA-CH5 activity was tested on cells expressing GLP-1, GLP-2, GIP or glucagon receptors. The ability to cross the blood-brain barrier (BBB) of DA-CH5, exendin-4, liraglutide or other dual receptor agonists was tested with fluorescein-labelled peptides. DA-CH5, exendin-4 and liraglutide were tested in the MPTP mouse model of PD.

Results: Analysing the receptor activating properties showed a balanced activation of GLP-1 and GIP receptors while not activating GLP-2 or glucagon receptors. DA-CH5 crossed the BBB better than other single or other dual receptor agonists. In a dose-response comparison, DA-CH5 was more effective than the GLP-1 receptor agonist exendin-4. When comparing the neuroprotective effect of DA-CH5 with Liraglutide, a GLP-1 analogue, both DA-CH5 and Liraglutide improved MPTP-induced motor impairments. In addition, the drugs reversed the decrease of the number of neurons expressing tyrosine hydroxylase (TH) in the SN, alleviated chronic inflammation, reduced lipid peroxidation, inhibited the apoptosis pathway (TUNEL assay) and increased autophagy -related proteins expression in the substantia nigra (SN) and striatum. Importantly, we found DA-CH5 was superior to Liraglutide in reducing microglia and astrocyte activation, improving mitochondrial activity by reducing the Bax/Bcl-2 ratio and normalising autophagy as found in abnormal expression of LC3 and p62.

Conclusion: The results demonstrate that the DA-CH5 is superior to liraglutide and could be a therapeutic treatment for PD.

Trial registration: ClinicalTrials.gov NCT02953665.

Keywords: Dopamine; growth factors; insulin; mitochondria; neuron; neuroprotection.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Exenatide / pharmacology
  • Glucagon-Like Peptide 1 / analysis
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Liraglutide / pharmacology*
  • Mice
  • Neuroprotective Agents / pharmacology*
  • Parkinson Disease / drug therapy
  • Parkinsonian Disorders / drug therapy*
  • Receptors, Gastrointestinal Hormone / agonists*

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Neuroprotective Agents
  • Receptors, Gastrointestinal Hormone
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide
  • gastric inhibitory polypeptide receptor

Associated data

  • ClinicalTrials.gov/NCT02953665