Trauma to Developing Brain-Oxidative Events and Recovery

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DESCRIPTION (provided by applicant): Traumatic brain injury is the leading cause of disability in children and is often associated with significant cognitive and motor deficits. Recent studies indicate that traumatic brain injury impairs motor and cognitive function to a greater extent in children less that 4 years of age than in older children. One explanation for this increased vulnerability may be related to the timing of the injury, which occurs during the critical period of development, characterized by rapid growth of neural structures. Although there has been a considerable effort directed toward understanding the pathobiology of traumatic brain injury in the mature adult brain, little is known about the consequences of traumatic brain injury in the child, particularly during the critical period of development. We hypothesize that traumatic brain injury during the critical period of development causes neuronal injury and death within specific regions of the brain, resulting in persistent functional deficits. We further hypothesize that oxidative stress, resulting from production of H202 and inadequate scavenging systems, are important determinants of neuronal injury and behavioral deficits in the immature, traumatized brain. Three aims are proposed. In the first aim we will develop a model of acute cortical contusion injury in the immature (postnatal day 21) mouse. Neuronal cell loss and glial reactivity, quantitatively defined at the light microscopic level, will be evaluated in concert with assessments of cognitive and motor function up to 6 months post-injury. In the second aim, we will measure indicators of oxidative stress/injury in this model, including lipid peroxidation and glutathione levels, H202 production, and antioxidants. In the third aim we will determine if reducing oxidative stress will limit neuronal injury and promote cognitive and motor recovery. Regional neuronal vulnerability and motor and cognitive deficits will be evaluated. Oxidative stress will be reduced by transgenic overexpression of glutathione peroxidase or by treatment with the spin-trap antioxidant PBN. These studies reflect a collaboration between Dr. Linda Noble, who has expertise in experimental traumatic brain injury, Dr. Donna Ferriero , an expert on mechanisms of oxidative injury in neonatal hypoxia-ischemia, and Dr. Jacob Raber, who has developed well defined, sensitive measures of cognitive and motor function in the mouse. This combined expertise offers a focused effort to better understand the vulnerability of the immature brain to traumatic injury and to develop the most optimal therapeutic approaches.