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

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 neuroprotective 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. Synopsis: Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy. A single peripheral administration of a GLP1 receptor agonist, used in the clinic to treat diabetes, significantly reduced brain infarct size and improved survival and locomotor function in a mouse model of neonatal HIE. GLP1 receptor agonists activated neuroprotective pathways and reduced markers of inflammatory response in the brain. This study is supportive of further investigating the clinical application of GLP1 receptor agonist for HIE but also more widely for other neurological diseases. Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy. [ABSTRACT FROM AUTHOR]