8 research outputs found

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

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    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

    Posttraumatic Reduction of Edema with Aquaporin-4 RNA Interference Improves Acute and Chronic Functional Recovery

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    Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood–brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site
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