8 research outputs found
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