TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

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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 (PPP/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 (PP and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P/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.