ObjectivesIn this study, we address a gap in knowledge regarding the therapeutic potential of acute treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist after severe brain trauma. Moreover, it remains still unknown whether GLP-1 treatment activates the protective, anti-neurodegenerative cAMP response element binding protein (CREB) pathway in the brain in vivo, and whether activation leads to observable increases in protective, anti-neurodegenerative proteins. Finally, we report the first use of a highly sensitive in vivo imaging agent to assess reactive species generation after brain trauma.Methods Severe trauma was induced with a stereotactic cryo-lesion in mice and thereafter treated with vehicle, liraglutide, or liraglutide + GLP-1 receptor antagonist. A therapeutic window was established and lesion size post-trauma was determined. Reactive oxygen species were visualized in vivo and quantified directly ex vivo. Hematological analysis was performed over time. Necrotic and apoptotic tone and neuroinflammation was assessed over time. CREB activation and CREB-regulated cytoprotective proteins were assessed over time.Results Lira treatment reduced lesion size by ∼50% through the GLP-1 receptor. Reactive species generation was reduced by ∼40-60%. Necrotic and apoptotic tone maintained similar to sham in diseased animals with Lira treatment. Phosphorylation of CREB was markedly increased by Lira in a GLP-1 receptor-dependent manner. CREB-regulated cytoprotective and anti-neurodegenerative proteins increased with Lira-driven CREB activation. Interpretation These results show that Lira has potent effects after experimental trauma in mice and thus should be considered a candidate for critical care intervention post-injury. Moreover, activation of CREB in the brain by Lira - described for the first time to be dependent on pathology - should be investigated further as a potential mechanism of action in neurodegenerative disorders.