1. ¹Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
2. ²Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
3. ³Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
4. ⁴Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
5. ⁵Vascular Medicine Research Unit, Brigham and Women's Hospital, Cambridge, Massachusetts, USA

Correspondence: Dr MJ Whalen, Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA. E-mail: MWhalen@Partners.org

⁶These two authors contributed equally.

Received 10 October 2006; Revised 1 February 2007; Accepted 9 February 2007; Published online 4 April 2007.

Abstract

Tumor necrosis factor-alpha (TNF) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNF, Fas, or both (TNF/Fas-/-), we hypothesized that TNF and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNF/Fas-/- mice had improved motor performance from 1 to 4 days (P<0.05), improved spatial memory acquisition at 8 to 14 days (P<0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P<0.05). Protection in TNF/Fas-/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNF before CCI, and TNF-/- mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P<0.05). Tumor necrosis factor-alpha/Fas-/- mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P<0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNF and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P<0.05 versus WT), suggesting that the beneficial effects of TNF/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNF and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNF/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.