Repurposing GLP-1RA Drugs for Modulating Sepsis-Associated Encephalopathy and Neurodegeneration

Repurposing GLP-1RA Drugs for Modulating Sepsis-Associated Encephalopathy and Neurodegeneration

Alvin Sherman Library

Sepsis, a life-threatening disorder caused by an exacerbated immune host response towards a pathogen, accounts for about 1 in 5 deaths worldwide with more than 11 million deaths. In septic pathophysiology, pathogen components interact with the receptors of immune and endothelial cells, causing the release of inflammatory signals. This results in a hyperinflammatory phase that leads to "leaky" blood vessels through vasodilation, which causes improper tissue perfusion and hypotension. If untreated, this can lead to multiorgan damage and can be especially damaging to vulnerable, non-regenerative organs such as the brain. Post-sepsis recovery has long term consequences in the central nervous system including sepsis-associated encephalopathy (SAE) and heightened risk for neurodegenerative disease development. SAE is a broader term for diffuse brain dysfunction and results in a wide range of symptoms including delirium, confusion, seizures, and in severe cases, coma. Resident brain immune cells, called the microglia, are activated resulting in functional changes that increase neuroinflammation in a positive feedback loop. This sepsis-induced neuroinflammation triggers the inflammasome, neuronal death through ferroptosis, synapse degradation, impairment of other glial cells, and demyelination, which are all factors that contribute to neurodegeneration. This systematic review aims to examine the possible application of glucagon-like peptide-1 receptor agonists (GLP-1RA) drugs as neuromodulators for post-sepsis neurological consequences. GLP-1RAs, which are commonly used to treat obesity and diabetes, have shown improvements in animal models of SAE, lowering neuroinflammation and neurodegenerative outcomes. Consequently, GLP-1RAs represent promising therapeutic potential in post-sepsis neurological recovery and mitigation of long-term neurodegenerative risk in sepsis survivors.