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10.3390/cells15141301
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Article

Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects

by
Yazhou Li
1,*,
Elliot J. Glotfelty
2,
Pathik Parekh
1,
Buyandelger Batsaikhan
1,
Weiming Luo
1,
Shelley N. Jackson
3,
Brandon K. Harvey
2 and
Nigel H. Greig
1,*
1
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
2
Cellular Stress and Inflammation Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
3
Translational Analytical Core, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
*
Authors to whom correspondence should be addressed.
Cells 2026, 15(14), 1301; https://doi.org/10.3390/cells15141301
Submission received: 27 May 2026 / Revised: 13 July 2026 / Accepted: 16 July 2026 / Published: 21 July 2026
(This article belongs to the Special Issue Brain Insulin Resistance in Neurodegenerative Disorders and Its Treatments)
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Abstract

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions.
Keywords: glucagon-like peptide-1 receptor (GLP-1R); neurodegeneration; neuroinflammation; neuroprotection; brain insulin resistance glucagon-like peptide-1 receptor (GLP-1R); neurodegeneration; neuroinflammation; neuroprotection; brain insulin resistance
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MDPI and ACS Style

Li, Y.; Glotfelty, E.J.; Parekh, P.; Batsaikhan, B.; Luo, W.; Jackson, S.N.; Harvey, B.K.; Greig, N.H. Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects. Cells 2026, 15, 1301. https://doi.org/10.3390/cells15141301

AMA Style

Li Y, Glotfelty EJ, Parekh P, Batsaikhan B, Luo W, Jackson SN, Harvey BK, Greig NH. Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects. Cells. 2026; 15(14):1301. https://doi.org/10.3390/cells15141301

Chicago/Turabian Style

Li, Yazhou, Elliot J. Glotfelty, Pathik Parekh, Buyandelger Batsaikhan, Weiming Luo, Shelley N. Jackson, Brandon K. Harvey, and Nigel H. Greig. 2026. "Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects" Cells 15, no. 14: 1301. https://doi.org/10.3390/cells15141301

APA Style

Li, Y., Glotfelty, E. J., Parekh, P., Batsaikhan, B., Luo, W., Jackson, S. N., Harvey, B. K., & Greig, N. H. (2026). Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects. Cells, 15(14), 1301. https://doi.org/10.3390/cells15141301

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