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: Andrew M Fukuda, Arash Adami, Viorela Pop, John A Bellone, Jacqueline S Coats, Richard E Hartman, Stephen Ashwal, Andre Obenaus, Jerome Badaut
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 33 Issue 10 Pg. 1621-32 (Oct 2013) ISSN: 1559-7016 [Electronic] United States
• PMID: 23899928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aqp4 protein, rat
• Aquaporin 4
• RNA, Small Interfering

Topics

• Animals
• Animals, Newborn
• Aquaporin 4 (antagonists & inhibitors, genetics)
• Behavior, Animal
• Brain Edema (etiology, metabolism, physiopathology, prevention & control)
• Brain Injuries (complications, metabolism, physiopathology)
• Gene Silencing
• Magnetic Resonance Imaging
• Microinjections
• RNA, Small Interfering (administration & dosage, genetics, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Recovery of Function