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Article

Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration

1
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
2
Cellular Stress and Inflammation Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(7), 872; https://doi.org/10.3390/biom14070872
Submission received: 29 May 2024 / Revised: 3 July 2024 / Accepted: 15 July 2024 / Published: 19 July 2024
(This article belongs to the Special Issue The Role of Microglia in Aging and Neurodegenerative Disease)

Abstract

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment.
Keywords: glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); glucagon; incretin mimetic; neuroinflammation; neurodegeneration; Alzheimer’s disease; Parkinson’s disease; microglia glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); glucagon; incretin mimetic; neuroinflammation; neurodegeneration; Alzheimer’s disease; Parkinson’s disease; microglia

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MDPI and ACS Style

Kopp, K.O.; Li, Y.; Glotfelty, E.J.; Tweedie, D.; Greig, N.H. Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration. Biomolecules 2024, 14, 872. https://doi.org/10.3390/biom14070872

AMA Style

Kopp KO, Li Y, Glotfelty EJ, Tweedie D, Greig NH. Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration. Biomolecules. 2024; 14(7):872. https://doi.org/10.3390/biom14070872

Chicago/Turabian Style

Kopp, Katherine O., Yazhou Li, Elliot J. Glotfelty, David Tweedie, and Nigel H. Greig. 2024. "Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration" Biomolecules 14, no. 7: 872. https://doi.org/10.3390/biom14070872

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