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The Journal of Neuroscience, August 1, 1999, 19(15):6248-6256
Exacerbation of Damage and Altered NF- B Activation in Mice
Lacking Tumor Necrosis Factor Receptors after Traumatic Brain
Injury
Patrick G.
Sullivan1, 2,
Annadora J.
Bruce-Keller1,
Alexander G.
Rabchevsky1,
Sylivia
Christakos4,
Daret
K. St.
Clair3,
Mark P.
Mattson1, 2, and
Stephen W.
Scheff1, 2
1 Sanders-Brown Center on Aging,
2 Department of Anatomy and Neurobiology, and
3 Graduate Center for Toxicology, University of Kentucky,
Lexington, Kentucky 40536-0230, and 4 Department of
Biochemistry and Molecular Biology, University of Medicine and
Dentistry of New Jersey Medical School, Newark, New Jersey 07103
Tumor necrosis factor  (TNF) is widely expressed in both
neurons and glia and has been shown to be upregulated after traumatic brain injury (TBI). TNF receptor activation results in activation of
the transcription factor nuclear factor  B (NF-B), which may serve
an antiapoptotic role via the induction of target genes manganese
superoxide dismutase (MnSOD) and/or calbindin. In the present study, we
used a controlled cortical impact model of TBI with pertinent lines of
transgenic mice to combine both morphological characterization and
molecular analysis to elucidate the role of TNF after TBI.
Measurements of both the lesion volume and the blood-brain barrier
breach indicated exacerbations in mice rendered genetically deficient
in both the p55 and p75 TNF receptors (TNFR-KO) compared with
wild-type animals. Additionally, animals genetically altered to
overexpress MnSOD showed a significant decrease in lesion volume
compared with that of control littermates, whereas no alterations were
observed in mice lacking the calcium-binding protein calbindin D28k.
Analysis of NF-B activation and relative levels of MnSOD revealed
delayed responses in the injured cortex of TNFR-KO animals compared
with wild-type animals, implying that endogenous TNF may be
neuroprotective after TBI.
Key words:
neurotrauma; blood-brain barrier; transgenic; cortical
impact; oxidative stress; TNF
Copyright © 1999 Society for Neuroscience 0270-6474/99/19156248-09$05.00/0
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