Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury.
Tumor necrosis factor alpha (TNFalpha) is widely expressed in both neurons and glia and has been shown to be upregulated after traumatic brain injury (TBI). TNFalpha receptor activation results in activation of the transcription factor nuclear factor kappaB (NF-kappaB), 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 TNFalpha 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 TNFalpha 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-kappaB 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 TNFalpha may be neuroprotective after TBI.
Sullivan
P G
PG
Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536-0230, USA.
Bruce-Keller
A J
AJ
Rabchevsky
A G
AG
Christakos
S
S
Clair
D K
DK
Mattson
M P
MP
Scheff
S W
SW
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D064092:Calbindin 1; D064026:Calbindins; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014949:Wounds, Nonpenetrating / Q000378:metabolism / Q000473:pathology
C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D064030:S100 Calcium Binding Protein G; D013482:Superoxide Dismutase