Posttraumatic Reduction of Edema with Aquaporin-4 RNA Interference Improves Acute and Chronic Functional Recovery
| Autor: | Jacqueline S Coats, Viorela Pop, Richard E. Hartman, Stephen Ashwal, Jérôme Badaut, John A. Bellone, Andrew M. Fukuda, Andre Obenaus, Arash Adami |
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| Rok vydání: | 2013 |
| Předmět: |
Programmed cell death
Pathology medicine.medical_specialty Microinjections Traumatic brain injury Brain Edema Rats Sprague-Dawley Edema medicine Animals Gene silencing Gene Silencing RNA Small Interfering Neuroinflammation Aquaporin 4 Behavior Animal business.industry Recovery of Function medicine.disease Magnetic Resonance Imaging Rats Astrogliosis medicine.anatomical_structure Animals Newborn Neurology Brain Injuries Original Article Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business Astrocyte |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 33:1621-1632 |
| ISSN: | 1559-7016 0271-678X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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