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Pathophysiology of Juvenile Traumatic Brain Injury: Role of Edema and a Potential Treatment


Traumatic brain injury (TBI) is caused by an external force to the head, resulting in damage to the brain. TBI is especially common in children and young adults and is associated with long-term mortality and morbidity. Juveniles seem to be at increased risk of developing cerebral edema after TBI partly due to higher water content and developmental differences in the brain's response to injury. Aquaporin-4 (AQP4) is the most abundant water channel in the brain and plays a critical role in edema formation. Edema formation can be attributed to cellular swelling (cytotoxic edema) or breakdown of the blood-brain barrier (BBB). This dissertation examined the lesion composition (percentage of blood and edema) after graded juvenile TBI (jTBI) and role of AQP4 in the normal and pathologic rodent brain. Using an established rodent model of focal jTBI, we characterized the composition of the lesion using magnetic resonance imaging (MRI). We found that 1 day after jTBI, the lesion was ~60% edema and ~40% blood. At 3 days, the edema volume decreased in all severity groups and the extravascular blood volume in the lesion remained unchanged. To understand water mobility in the brain after jTBI, we first evaluated the effects of knocking down AQP4 using RNA interference in an uninjured juvenile rodent brain. We demonstrated that a 27% decrease in AQP4 protein expression, induced by small interfering RNA against AQP4 (siAQP4), lead to a 50% reduction in water mobility using We then investigated the effect of siAQP4 injection in a juvenile rodent brain after TBI. We identified improved neurologic testing and physiologic measures, including reduced edema formation, neuronal cell death, astrogliosis, and BBB, in rat pups treated with siAQP4. Given these results, knock down of AQP4 may prove to be an effective therapy in the early time course after jTBI.

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