Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 27, Issue 11, Pages 1806-1818Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600487
Keywords
brain trauma; genetics; knockout; neuroprotection; Fas; immature
Categories
Funding
- NINDS NIH HHS [R01 NS40529, R01 NS47447, R01 NS48422] Funding Source: Medline
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Tumor necrosis factor-alpha (TNF alpha) 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 alpha, Fas, or both (TNF alpha/ Fas -/-), we hypothesized that TNF alpha and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNF alpha/ 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 alpha/Fas -/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNF alpha before CCI, and TNF alpha -/- 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 6h ( 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 alpha 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 alpha/ Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNF alpha and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNF alpha/ Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.
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