Diabetes drugs activate neuroprotective pathways in models of neonatal hypoxic-ischemic encephalopathy

Poupon-Bejuit, Laura; Geard, Amy; Millicheap, Nathan; Rocha-Ferreira, Eridan; Hagberg, Henrik; Thornton, Claire; Rahim, Ahad A

Abstract

Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short-and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuro-protective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE.

Citation

Poupon-Bejuit, L., Geard, A., Millicheap, N., Rocha-Ferreira, E., Hagberg, H., Thornton, C., & Rahim, A. A. (2024). Diabetes drugs activate neuroprotective pathways in models of neonatal hypoxic-ischemic encephalopathy. EMBO Molecular Medicine, https://doi.org/10.1038/s44321-024-00079-1

• Journal Article Type: Article
• Acceptance Date: May 7, 2024
• Online Publication Date: May 23, 2024
• Publication Date: 2024
• Deposit Date: May 23, 2024
• Publicly Available Date: May 31, 2024
• Print ISSN: 1757-4676
• Electronic ISSN: 1757-4684
• Publisher: EMBO Press
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s44321-024-00079-1
• Keywords: GLP1-R Agonists; Semaglutide; Exendin-4; Neonatal Hypoxic- ischaemic Encephalopathy; Neuroprotective Mechanisms Subject Category Neuroscience