Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

• Published in: Nature communications Vol. 3; no. 1; p. 849
• Main Authors: Campbell, Matthew, Hanrahan, Finnian, Gobbo, Oliviero L., Kelly, Michael E., Kiang, Anna-Sophia, Humphries, Marian M., Nguyen, Anh T.H., Ozaki, Ema, Keaney, James, Blau, Christoph W., Kerskens, Christian M., Cahalan, Stephen D., Callanan, John J., Wallace, Eugene, Grant, Gerald A., Doherty, Colin P., Humphries, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.05.2012; Nature Publishing Group
• Subjects: 631/154/51/391/505; 631/378/1689; 692/699/375/1345; Animals; Blood-Brain Barrier - metabolism; Brain Edema - diagnostic imaging; Brain Edema - etiology; Brain Edema - therapy; Brain Injuries - complications; Brain Injuries - diagnostic imaging; Child; Claudin-5; Claudins - genetics; Claudins - metabolism; Cognition - physiology; Humanities and Social Sciences; Humans; Intracranial Pressure - physiology; Male; Mice; multidisciplinary; RNA Interference; Science; Science (multidisciplinary); Tomography, X-Ray Computed
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms1852

Traumatic brain injury is the leading cause of death in children and young adults globally. Malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RNA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology. Claudin-5 is a component of tight junctions and has important roles in mediating the permeability of the blood-brain barrier. Campbell and co-workers administer short interfering RNA against claudin-5 in a model of brain injury, finding that it enhances water movement from the brain to the blood and alleviates swelling.