The novel GLP-1/GIP dual receptor agonist DA5-CH is superior to tirzepatide and exendin-4 in the 6-OHDA Parkinson rat model

  • Front Endocrinol (Lausanne). 2026 May 5:17:1825379. doi: 10.3389/fendo.2026.1825379.
Zhang Lingyu  1 ,  Feng Peng  2 ,  Zhong Wanting  3 ,  Jin Qianqian  4 ,  Zijuan Zhang  5 ,  Bo Bai  2 ,  Guofang Xue  2 ,  Christian Hölscher  2
Affiliations
  • 1. Experimental Animal Center of Shanxi Medical University, Shanxi Key Laboratory of Human Disease and Animal Models, Taiyuan, Shanxi, China.
  • 2. Second Hospital, Neurology Department, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 3. School of Medical Science, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 4. Department of Forensic Pathology, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 5. School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
PMID: 42165019 DOI: 10.3389/fendo.2026.1825379
Abstract

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no cure. Diabetes is one of the risk factors for developing PD. Tirzepatide is a novel long-acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist that is on the market as a treatment for diabetes. Importantly, two phase II trials in PD patients showed good effects with the GLP-1 Receptor agonists Exendin-4 and Lixisenatide.

Methods: We have developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier (BBB) at a higher rate than Tirzepatide. Here, we tested Exendin-4, Tirzepatide and DA5-CH in the 6-OHDA-lesion rat model of PD. The drug treatment was daily (10 nmol/kg, IP.) for 30 days.

Results: DA5-CH was more effective than Tirzepatide or Exendin-4. In the substantia nigra, dopaminergic neurons were protected, with DA5-CH being most effective. Dopamine levels in the striatum were normalized by DA5-CH, while Exendin-4 was less effective, and Tirzepatide was ineffective. The inflammation response in the lesioned striatum was reduced by the drugs as shown in reduced IL-6 and TNF-α levels, with DA5-CH being more effective than Exendin-4, and Tirzepatide showing minimal effects. Furthermore, the α-synuclein levels in the substantia nigra were reduced by DA5-CH, superior to Exendin-4 and Tirzepatide.

Discussion: Therefore, DA5-CH was more effective and may be a better therapeutic drug for neurodegenerative disorders such as PD compared to Tirzepatide or Exendin-4.

Keywords
GLP-1; cytokines; growth factor; inflammation; insulin; mitochondria.
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