Effects of Docosahexaenoic Acid on Oxidative Stress White Matter Injury and Brain Inflammation in a Pre-Clinical Model of Pediatric TBI

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PROJECT SUMMARY Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children. Agents that decrease oxidative stress and inflammation may decrease neurologic disability after TBI, particularly in children. Docosahexaenoic Acid, or DHA, is a candidate therapy for childhood TBI. In our established rat pup model of pediatric TBI, DHA improved functional outcome and decreased brain oxidative stress, white matter injury and inflammation. DHA is available as a nutritional supplement for infants and children. However, DHA cannot be tested in clinical TBI trials until critical knowledge gaps are breached. Effects of DHA on oxidative stress, white matter integrity and inflammation in the human brain after TBI are unknown, as are data on optimal DHA dosing in humans after TBI. DHA safety and efficacy in the immature brain cannot be predicted based on adult studies. Relative to the adult brain, the immature brain has a more vigorous inflammatory response and a lesser antioxidant capacity. DHA is a direct antioxidant, but at high doses its numerous double bonds could instead magnify free radical damage after pediatric TBI. We propose to address these unknowns using fluid-percussion injury (FPI) in the piglet, a well-established model of pediatric TBI. Immature pig and human brains share striking nutritional, anatomic and developmental similarities. Piglet FPI, unlike rodent TBI, allows clinically relevant monitoring using serial cerebrospinal fluid (CSF), urine and blood sampling. We have characterized piglet FPI of moderate severity and established a methodology of DHA administration and biofluid sampling. We hypothesize that acute DHA administration will decrease oxidative stress, white matter damage and inflammation, associated with biomarkers of efficacy and toxicity, in piglets after FPI. We will use 4-week old piglets exposed to FPI or SHAM surgery, treated with one of two DHA doses (40 or 200mg/kg/day) or vehicle (VEH). We will measure biomarkers of oxidative stress, white matter damage and inflammation in CSF, urine and blood samples taken at 1, 3 and 7 days after FPI. We will compare biomarker results between DHA dosing groups, and to day 7 brain assays of neuronal death, white matter damage, inflammation and oxidative injury to proteins, lipids and DNA in the brain. This proposal is significant because it will lay the groundwork for efficacy and safety monitoring during future clinical trials of candidate neuroprotectants, such as DHA, in children after TBI by providing data on DHA dosing and biomarkers of efficacy and toxicity in a translational model. It is innovative because little is known about DHA after acute brain injury during development or about the utility of biomarkers in pediatric TBI. It will impact the field by providing clinically relevant measures of efficacy and safety needed to design a Phase II trial and, ultimately, an interventional trial of DHA with the potential to decrease the burden of acquired neurologic injury after pediatric TBI.