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

Area of Science:

• Neuroscience
• Neonatal Medicine
• Pharmacology

Background:

• Hypoxic-ischaemic encephalopathy (HIE) is a severe neonatal condition caused by reduced oxygen and blood flow to the brain.
• HIE leads to significant infant mortality and long-term neurological deficits.
• Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, known for type 2 diabetes treatment, have demonstrated neuroprotective properties in preclinical models.

Purpose of the Study:

• To investigate the neuroprotective and anti-inflammatory effects of GLP1-R agonists in a neonatal mouse model of HIE.
• To explore the underlying molecular mechanisms of GLP1-R agonist-mediated neuroprotection.

Main Methods:

• Neonatal mice (post-natal day 10) underwent surgically induced hypoxic-ischaemic (HI) brain injury.
• Mice received immediate systemic administration of exendin-4 or semaglutide (GLP1-R agonists).
• Neuropathology, survival rates, locomotor function, PI3/AKT signaling pathway, and cAMP levels were assessed.

Main Results:

• Systemic administration of exendin-4 or semaglutide significantly improved neurological outcomes in mice with HI brain injury.
• GLP1-R agonists enhanced short- and long-term neuropathology, increased survival rates, and improved locomotor function.
• Neuroprotection was associated with PI3/AKT pathway upregulation and increased cAMP levels, indicating reduced inflammation.

Conclusions:

• GLP1-R agonists exert significant neuroprotective and anti-inflammatory effects in neonatal HIE.
• The findings support the potential clinical application of GLP1-R agonists for treating HIE in infants.
• These agents may also be beneficial for other neurological conditions involving brain injury.