Effect of intranasal HB-EGF treatment on brain glucose metabolism and inflammation after TBI in the developing brain

Pediatric traumatic brain injury (TBI) is the leading cause of significant life-long cognitive and sensorimotor disabilities. To date, acute care is limited to supportive measures, and there continues to be a lack of targeted therapeutics to improve neurologic outcome. Metabolic crisis from impaired oxidative glucose metabolism and inflammation are the hallmarks of TBI. The dysregulation and impaired mitochondrial function results in the depletion of energy in the form of ATP. Simultaneously, TBI is characterized by activation of microglia – the resident macrophages of the brain – to clear damaged tissue. The ongoing secondary injury due to mitochondrial dysfunction and decreased cell viability signal the microglia to remain in a persistently activated state, becoming dysregulated and further propagating the inflammatory cascade. Targeted therapy that improves oxidative glucose metabolism and limits inflammation is crucial. Recent data from our lab found that a neurotrophic growth factor, heparin-binding epidermal growth factor (HB-EGF) increases pathways responsible for oxidative phosphorylation and decreases inflammation. Our preliminary experiments suggest that intranasal HB-EGF quickly enters the brain and improves mitochondrial health. Therefore, we hypothesize that treatment with intranasal HB-EGF after moderate-severe pediatric TBI will improve brain oxidative glucose metabolism and mitochondrial function while decreasing inflammation. In the first aim, we will determine whether treatment with intranasal HB-EGF after TBI improves brain oxidative glucose metabolism and delineate the regional and temporal effects of intranasal HB-EGF after developmental TBI. In the second aim, we will determine whether treatment with intranasal HB-EGF in the acute period after TBI decreases inflammation. The impact of this project is that we will gain a greater understanding of the regulation of metabolism and inflammation from treatment with HB-EGF in normal and injured developing brain.