Experimental Brain Injury Induces Regionally Distinct Apoptosis during the Acute and Delayed Post-Traumatic Period

Conti, Alana C.; Raghupathi, Ramesh; Trojanowski, John Q.; McIntosh, Tracy K.

doi:10.1523/jneurosci.18-15-05663.1998

Cited by 498 publications

(347 citation statements)

References 67 publications

Supporting

Mentioning

307

Contrasting

Unclassified

Order By: Relevance

“…9,11,38 Bcl-2, a protein with anti-apoptotic activity, is expressed in neurons which survive different types of injury in vivo such as ischemia 6 and CCI. 8 In the present study, bcl-2 mRNA expression was significantly decreased at 24 h post-injury, returning to baseline levels by 48 h. Interestingly, bax mRNA levels were not altered after injury, suggesting that the cellular ratio of bax:bcl-2 protein may have increased, thereby favoring initiation of apoptosis which has been shown to occur after TBI in the rat.…”

Section: Discussionmentioning

confidence: 99%

“…8 In the present study, bcl-2 mRNA expression was significantly decreased at 24 h post-injury, returning to baseline levels by 48 h. Interestingly, bax mRNA levels were not altered after injury, suggesting that the cellular ratio of bax:bcl-2 protein may have increased, thereby favoring initiation of apoptosis which has been shown to occur after TBI in the rat. 9,57 Ubiquitin plays a vital role in the targeted degradation of damaged proteins and is also essential for the cellular stress-response . Several other temporal profiles of expression were observed including no regulation (E) and a post-injury increase (H).…”

Section: Discussionmentioning

confidence: 99%

“…13,26,71,73 Alterations in the expression and activity of cell death genes such as caspase-1 and caspase-3 have also been documented after CCI. 70 Morphological evidence of apoptotic cell death has been demonstrated in various models of TBI 8,9,57,70 suggesting that regulation of apoptotic pathways may contribute significantly to the post-traumatic sequelae. Genes associated with inflammatory mediators such as the cytokines interleukin-1b (IL-1b) and tumor necrosis factora (TNF-a) have been implicated in both apoptotic and necrotic cell death pathways, and their expression has been shown to be up-regulated after fluid percussion injury (FPI) in the rat.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

et al. 2000

View full text Add to dashboard Cite

Abstract-The expression of a large panel of selected genes hypothesized to play a central role in post-traumatic cell death was shown to be differentially altered in response to a precisely controlled, mechanical injury applied to an organotypic slice culture of the rat brain. Within 48 h of injury, the expression of nerve growth factor messenger RNA was significantly increased whereas the levels of bcl-2, a-subunit of calcium/calmodulin-dependent protein kinase II, cAMP response element binding protein, 65,000 mol. wt isoform of glutamate decarboxylase, 1b isoform of protein kinase C, and ubiquitin messenger RNA were significantly decreased. Because the expression levels of a number of other messenger RNAs such as the neuron-specific amyloid precursor protein, b 2 microglobulin, bax, bcl xl , brain-derived neurotrophic factor, cyclooxygenase-2, interleukin-1b, interleukin-6, tumor necrosis factor-a, receptor tyrosine kinase A, and receptor tyrosine kinase B were unaffected, these selective changes may represent components of an active and directed response of the brain initiated by mechanical trauma.Interpretation of these co-ordinated alterations suggests that mechanical injury to the central nervous system may lead to disruption of calcium homeostasis resulting in altered gene expression, an impairment of intracellular cascades responsible for trophic factor signaling, and initiation of apoptosis via multiple pathways. An understanding of these transcriptional changes may contribute to the development of novel therapeutic strategies to enhance beneficial and blunt detrimental, endogenous, post-injury response mechanisms. ᭧ 2000 IBRO. Published by Elsevier Science Ltd.Key words: genomic expression, in vitro model, traumatic brain injury, organotypic culture, stretch injury, cDNA array.The primary mechanical event associated with traumatic injury to the CNS initiates a cascade of molecular and cellular events which include changes in gene expression, culminating in cell dysfunction and/or death. Although the initial injury occurs in less than 1 s, the post-traumatic sequelae may take hours or days to develop, thereby providing an opportunity to therapeutically attenuate detrimental or augment beneficial endogenous responses in an attempt to limit resultant cell death. A detailed analysis of these specific molecular events may aid in the rational development of novel therapies for the brain-injured patient. Many genes which have been reported to be up-regulated following experimental models of traumatic brain injury (TBI), such as c-fos, c-jun, junB or zif/ 268, 24,54,58,69 are transcription factors that control the expression of other genes, suggesting that the expression of a large number of genes, including those involved in cell death or survival, may be affected by trauma.In this regard, expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), necessary for neuronal and other cell survival, has been shown to be increased after controlled cortical impact (CCI) injury in the rat. ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

et al. 2000

View full text Add to dashboard Cite

show abstract

“…13 Theshown to initiate a cascade of secondary or delayed cellular damage and death. 14,15 The elucidation of the mechanisms underlying this secondary damage promises to enable researchers to design more effective treatments for head-injured patients to complement prevention efforts. 16 Several conventional molecular biology techniques have traditionally enabled investigators to assess whether a particular gene may be involved with various physiological and disease processes by measuring the abundance of its corresponding mRNA transcript.…”

Section: Introductionmentioning

confidence: 99%

Methodological Considerations Regarding Single-Cell Gene Expression Profiling for Brain Injury

et al. 2004

Self Cite

View full text Add to dashboard Cite

Genomic microarrays are rapidly becoming ubiquitous throughout a wide variety of biological disciplines. As their use has grown during the past few years, many important discoveries have been made in the fields of central nervous system (CNS) injury and disease using this emerging technology. In addition, single-cell mRNA amplification techniques are now being used along with microarrays to overcome many of the difficulties associated with the cellular heterogeneity of the brain. This development has extended the utility of gene expression profiling and has provided researchers with exciting new insights into the neuropathology of CNS injury and disease at a molecular and cellular level. New methodological, standardization, and statistical techniques are currently being developed to improve the reproducibility of microarrays and facilitate the analysis of large amounts of data. In this review, we will discuss the application of these techniques to experimental, clinically relevant models of traumatic brain injury.

show abstract

“…Moreover, apoptosis is induced as a secondary phenomenon in several neuronal populations in the CNS after axonal lesions, for example, in traumatic injuries. 10,11 The apoptotic program is executed by a family of specialized proteases, called caspases. 1,12 These proteins are present in cells as inactive zymogens which are activated through proapoptotic signals.…”

Section: Introductionmentioning

confidence: 99%

Transduction of axotomized retinal ganglion cells by adenoviral vector administration at the optic nerve stump: an in vivo model system for the inhibition of neuronal apoptotic cell death

et al. 1999

View full text Add to dashboard Cite

Axotomy of the rat optic nerve leads to apoptotic cell death present beyond the time-point of detectable transcription of retinal ganglion cells (RGCs). We have used adenoviral of the p35 transgene, we conclude that apoptosis has been vectors to transduce RGCs from the cut optic nerve stump, efficiently inhibited. In addition, we observed that transduca paradigm in which only those neurons are transduced tion with two control vectors without a transgene in E1 also which are directly affected by the axonal lesion. Transresulted in a minor but significant RGC rescue, implicating genes encoded by the vectors were p35 and CrmA, which neuroprotective effects due to adenoviral transduction are potent intracellular anti-apoptotic proteins. We found itself. This system will be useful in dissecting the pathways that p35, but not CrmA exerted significant rescue effects leading to neuronal cell death after axonal lesions and in on RGCs 14 days after axotomy. Expression of the transthe evaluation of the important question whether the genes was driven by the murine CMV (MCMV) promoter. cellular suicide program can be reverted to survival by The respective mRNAs were detectable 7 days but not 14 therapeutic gene delivery. days after transduction. Since surviving RGCs were

show abstract

Experimental Brain Injury Induces Regionally Distinct Apoptosis during the Acute and Delayed Post-Traumatic Period

Cited by 498 publications

References 67 publications

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

Traumatic injury induces differential expression of cell death genes in organotypic brain slice cultures determined by complementary DNA array hybridization

Methodological Considerations Regarding Single-Cell Gene Expression Profiling for Brain Injury

Transduction of axotomized retinal ganglion cells by adenoviral vector administration at the optic nerve stump: an in vivo model system for the inhibition of neuronal apoptotic cell death

Contact Info

Product

Resources

About