Traumatic brain injury (TBI) is a major public health concern with consequences including long-term loss of function or death. Accordingly, there is a significant need for improved treatments and other means for improving outcomes in TBI, especially in small children who are particularly likely to suffer such an injury. Mechanisms of TBI include inflammation, blood-brain barrier disruption, and neuronal death. The n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) has anti- inflammatory and anti-apoptotic activities. Diet n-3 PUFA content influences the levels of DHA that are incorporated into tissues, including the brain, where DHA continues to accumulate into at least the second year of life. The American diet is notably low in n-3 PUFAs;thus, Americans are at particular risk of having low tissue DHA levels. Acute administration of DHA improves outcomes in animal models of spinal cord injury and stroke. However, it is not known whether DHA has beneficial effects in TBI or whether diet n-3 content, and thus tissue DHA levels, influence TBI outcomes. The PIs'overall goal is to improve outcomes of TBI in young children. The objective of this application is to determine the effects of diet n-3 PUFA content, acute DHA treatment, and their interaction on outcomes in a rat model of TBI in toddlers. The PIs hypothesize that low diet n-3 PUFA content will be associated with poorer TBI outcomes, that acute DHA treatment after TBI will improve outcomes, and that acute DHA treatment and diet n-3 PUFA content will interact to affect outcomes in TBI. An innovative approach, integrating nutritional and neurobiological methods will be used to pursue the following Specific Aims: 1) Determine the effects of diet n-3 PUFA content on outcomes of TBI and 2) Determine the effects of acute DHA administration on outcomes of TBI in rats fed diets varying in n-3 PUFA content. Disruption of the blood-brain barrier, which is central to the pathological sequelae after TBI, and functional motor deficits and recovery, will be assessed. Expected outcomes include readily translatable findings on the potential utility of DHA treatment and/or increased dietary n-3 PUFA content in improving outcomes in pediatric TBI, and greater understanding of the role of DHA in the central nervous system with respect to inflammation, maintenance of the blood-brain barrier, and neuronal survival/death. Such findings may be anticipated to form a basis for future clinical studies that lead to novel therapeutic and/or preventative interventions to improve outcomes in pediatric TBI. These data will also form a platform from which to launch expanded basic studies of mechanisms underlying the beneficial effects of DHA in TBI, which may be anticipated to lead to the identification of novel targets for therapeutic intervention in TBI. Relevance: Traumatic brain injury affects at least 1.4 million Americans each year and is a significant cause of death and long-term disability. Children 0-4 years old are at the highest risk. This study seeks to identify means to improve outcomes of TBI in young children.
- Relevance Statement Traumatic brain injury affects at least 1.4 million Americans each year and is a significant cause of death and long-term disability. Children 0-4 years old are at the highest risk. This study seeks to identify means to improve outcomes of TBI in young children.
|Russell, K L; Berman, N E J; Gregg, P R A et al. (2014) Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. Prostaglandins Leukot Essent Fatty Acids 90:5-11|
|Russell, Kristin L; Berman, Nancy E J; Levant, Beth (2013) Low brain DHA content worsens sensorimotor outcomes after TBI and decreases TBI-induced Timp1 expression in juvenile rats. Prostaglandins Leukot Essent Fatty Acids 89:97-105|
|Russell, Kristin L; Kutchko, Katrina M; Fowler, Stephen C et al. (2011) Sensorimotor behavioral tests for use in a juvenile rat model of traumatic brain injury: assessment of sex differences. J Neurosci Methods 199:214-22|