A review and rationale for the use of genetically engineered animals in the study of traumatic brain injury

The mechanisms underlying secondary cell death after traumatic brain injury (TBI) are poorly understood. Animal models of TBI recapitulate many clinical and pathologic aspects of human head injury, and the development of genetically engineered animals has offered the opportunity to investigate the specific molecular and cellular mechanisms associated with cell dysfunction and death after TBI, allowing for the evaluation of specific cause-effect relations and mechanistic hypotheses. This article represents a compendium of the current literature using genetically engineered mice in studies designed to better understand the posttraumatic inflammatory response, the mechanisms underlying DNA damage, repair, and cell death, and the link between TBI and neurodegenerative diseases

Immunohistochemical characterization of Fas (CD95) and Fas Ligand (FasL-CD95L) expression in the injured brain: Relationship with neuronal cell death and inflammatory mediators

Traumatic brain injury causes progressive tissue atrophy and consequent neurological dysfunction, resulting from neuronal cell death in both animal models and patients. Fas (CD95) and Fas ligand (FasL/CD95L) are important mediators of apoptosis. However, little is known about the relationship between Fas and FasL and neuronal cell death in mice lacking the genes for inflammatory cytokines. In the present study, double tumor necrosis factor/lymphotoxin-a knockout (–/–) and interleukin-6–/– mice were subjected to closed head injury (CHI) and sacrificed at 24 hours or 7 days postinjury. Consecutive brain sections were evaluated for Fas and FasL expression, in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick end-labeling; TUNEL), morphologic characteristics of apoptotic cell death and leukocyte infiltration. A peak incidence of TUNEL positive cells was found in the injured cortex at 24 hours which remained slightly elevated at 7 days and coincided with maximum Fas expression. FasL was only moderately increased at 24 hours and showed maximum expression at 7 days. A few TUNEL positive cells were also found in the ipsilateral hippocampus at 24 hours. Apoptotic, TUNEL positive cells mostly co-localized with neurons and Fas and FasL immunoreactivity. The amount of accumulated polymorphonuclear leukocytes and CD11b positive cells was maximal in the injured hemispheres at 24 hours. We show strong evidence that Fas and FasL might be involved in neuronal apoptosis after CHI. Furthermore, Fas and FasL upregulation seems to be independent of neuroinflammation since no differences were found between cytokine–/– and wild-type mice

Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury

OBJECTIVE: Using the neural stem cell (NSC) clone C17.2, we evaluated the ability of transplanted murine NSCs to attenuate cognitive and neurological motor deficits after traumatic brain injury. METHODS: Nonimmunosuppressed C57BL/6 mice (n = 65) were anesthetized and subjected to lateral controlled cortical impact brain injury (n = 52) or surgery without injury (sham operation group, n = 13). At 3 days postinjury, all brain-injured animals were, reanesthetized and, randomized to receive stereotactic injection of NSCs or control Cells (human embryonic kidney cells) into the cortex-hippocampus interface in either the ipsilateral-or the contralateral hemisphere. One group of animals (n = 7) was killed. at either 1 or 3 weeks postinjury to assess NSC survival in the acute posttraumatic period. Motor function was evaluated at weekly intervals for 12 weeks in the remaining animals, and cognitive (i.e., learning) deficits were assessed at 13 and 12 weeks after transplantation. RESULTS: Brain-injured animals that, received either ipsilateral or contralateral NSC transplants showed significantly improved motor function in selected tests as compared with human embryonic kidney cell-transplanted animals during the 12-week observation period. Cognitive, dysfunction was unaffected by transplantation at either 3 or. 12 weeks postinjury. Histological analyses showed that NSCs survive for as long as 13 weeks after transplantation and were detected in the hippocampus and/or cortical areas adjacent to the, injury cavity. At 13 weeks, the, NSCs transplanted ipsilateral to the impact site expressed neuronal (NeuN) or astrocytic (glial fibrillary acidic protein) markers, but not, markers of oligodendrocytes (2'3'cyclic nucleotide 3'-phoshodiesterase), whereas, the contralaterally transplanted NSCs expressed neuronal but not glial markers (double-labeled immunofluorescence and confocal microscopy). CONCLUSION: These data suggest that transplanted NSCs can survive in the traumatically injured brain, differentiate into neurons and/or glia, and attenuate motor dysfunction after traumatic brain injury