title: Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery.
abstract: 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.
authors.affiliation: 1] Department of Physiology, Loma Linda University, Loma Linda, California, USA [2] Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, California, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fukuda
authors.forename: Arash
authors.initials: A
authors.lastname: Adami
authors.forename: Viorela
authors.initials: V
authors.lastname: Pop
authors.forename: John A
authors.initials: JA
authors.lastname: Bellone
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Coats
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hartman
authors.forename: Stephen
authors.initials: S
authors.lastname: Ashwal
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.forename: Jerome
authors.initials: J
authors.lastname: Badaut
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D001522:Behavior, Animal; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D020868:Gene Silencing; D008279:Magnetic Resonance Imaging; D008845:Microinjections; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D034741:RNA, Small Interfering
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