Trauma to developing brain: model refinement and therapeutic intervention

University Of California, San Francisco, San Francisco CA

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Abstract

Traumatic brain injury (TBI) is the most frequent cause of acquired brain injury, mortality, and morbidity in young children. A key obstacle to improved outcome of pediatric TBI is the paucity of translational research to identify innovative therapy. Here we address this obstacle by validating a murine model of trauma to the immature brain using clinically relevant measures, as defined in parallel studies in a pediatric population, and consider the efficacy of a matrix metalloproteinase (MMP) inhibitor in maintaining long-term grey and white matter integrity and preserving cognitive development after experimental TBI. In Specific Aim 1, using long term follow-up of 26 adolescents who sustained moderate to severe TBI at age 2-4 years, we propose brain imaging techniques to measure brain region volumes and white matter integrity at adolescence, focusing on the cortex, hippocampus and corpus callosum, structures that show acute damage in both animal models and children. Using a virtual maze task analogous to the Morris Water Maze employed to measure memory in our murine model, we will assess navigation and spatial memory in the adolescents who sustained early TBI. To assess the effects of frontal, temporal, and diffuse pathology, we will evaluate executive cognitive functions and overall functional status in the adolescents and analyze the relation of brain imaging findings to the cognitive outcome data. In Specific Aim 2, mice at postnatal day (pnd) 21 will be subjected to TBI and treated thereafter with the MMP inhibitor GM6001. We will first define an optimal dose and timing of administration of this drug based upon subacute anatomical measures of neuroprotection. We will then determine if this optimal dose/timing improves longer-term outcomes in mid and late adolescent mice who sustained injury at pnd 21. Stereologic and functional assays, designed to parallel the clinical measures in Aim 1, will be used to assess the consequences of treatment on cortex, hippocampus, and corpus callosum volumes and preservation of hippocampal neuronal populations, and to evaluate cognitive function using the Morris Water Maze. At the completion of these studies, we will have evaluated the efficacy of GM6001 in an animal model of TBI using outcomes validated in the pediatric population, a necessary first step toward advancing treatment of acute TBI in young children and mitigating the long term effects on cognitive development. Moreover, our introduction of measuring navigation and spatial memory to test hippocampal function in adolescents who sustained early TBI could also potentially advance clinical assessment techniques in this population.