Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss

Carmel, Jason B.; Galante, Anthony; Soteropoulos, Patricia; Tolias, Peter; Recce, Michael; Young, Wise; Hart, Ronald P.

doi:10.1152/physiolgenomics.00074.2001

Cited by 141 publications

(123 citation statements)

References 53 publications

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“…Furthermore Benn et al (77) have discovered that Hsp27 is up-regulated and phosphorylated after nerve injury, and these process are required for neuronal survival. Our present results are consistent with previous reports (24) where it is stated that the amount of Hsp27 increases in the spinal cords of SCI rats ( Fig. 3 and Table II).…”

Section: Discussionsupporting

confidence: 94%

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Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Tsai¹,

Shen²,

Kuo

et al. 2008

Molecular & Cellular Proteomics

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Acidic fibroblast growth factor (aFGF; also known as FGF-1) is a potent neurotrophic factor that affects neuronal survival in the injured spinal cord. However, the pathological changes that occur with spinal cord injury (SCI) and the attribution to aFGF of a neuroprotective effect during SCI are still elusive. In this study, we demonstrated that rat SCI, when treated with aFGF, showed significant functional recovery as indicated by the Basso, Beattie, and Bresnahan locomotor rating scale and the combined behavior score (p < 0.01-0.001). Furthermore proteomics and bioinformatics approaches were adapted to investigate changes in the global protein profile of the damaged spinal cord tissue when experimental rats were treated either with or without aFGF at 24 h after injury. We found that 51 protein spots, resolvable by two-dimensional PAGE, had significant differential expression. Using hierarchical clustering analysis, these proteins were categorized into five major expression patterns. Noticeably proteins involved in the process of secondary injury, such as astrocyte activation (glial fibrillary acidic protein), inflammation (S100B), and scar formation (keratan sulfate proteoglycan lumican), which lead to the blocking of injured spinal cord regeneration, were down-regulated in the contusive spinal cord after treatment with aFGF. We propose that aFGF might initiate a series of biological processes to prevent or attenuate secondary injury and that this, Spinal cord injury (SCI)1 is a costly disease as well as the most frequent cause of mortality and morbidity in every medical care system around the world (1, 2). Traumatic axonal injury is a primary sequela of contusive SCI and is characterized by axonal swelling and disconnection of the ascending sensory and descending motor tracts (3). Contusive SCI seems to initiate a complicated cascade of pathophysiological changes, a process called secondary injury, including fiber deformation, increased vascular permeability, local ischemia, intraneuronal edema, and local demyelination. Moreover traumatic axonal injury typically involves a disruption of the axonal membrane, and this results in up-regulation of the entry of calcium, the influx of which initiates calpain activation (4, 5) and mitochondrial injury/swelling (6), resulting in cytochrome c release and caspase activation (7). Simultaneously the proliferation and hypertrophy of astrocytes around the injury site are characterized by increased immunoreactivity to glial fibrillary acidic proteins (GFAPs) (8).Although many studies have focused on revealing the pathophysiology of SCI, the exact molecular mechanisms and the biochemical pathways that mediate secondary injury remain sketchy (9). Spinal cord injury often causes permanent neurological deficits mostly because the injured neurons lack regenerative ability, and the series of destructive processes that follow SCI results in a second wave of cell death and spreading tissue loss (10). Therefore, studies of the stimulaFrom the ‡Institute

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Section: Discussionsupporting

confidence: 94%

“…Recently microarray experiments have further demonstrated that Rab3A is decreased 6.8-fold after SCI (24). Furthermore we found that a substantial amount of Rab-GDI can be detected using 2D PAGE analysis in the SCI rats but not in the shams at 24 h after operation.…”

Section: Discussionsupporting

confidence: 48%

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Tsai¹,

Shen²,

Kuo

et al. 2008

Molecular & Cellular Proteomics

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“…Previous reports have suggested that p53 (Saito et al, 2000) and p53-dependent signaling (Carmel et al, 2001;Di Giovanni et al, 2003;Byrnes et al, 2006) are activated in both neuronal and glial cells following spinal cord injury (SCI). In addition, we previously found that p53-dependent target genes, including DNA damage, cell cycle, and axonal plasticityrelated molecules are triggered mainly between 1 and 7 d following injury (Di Giovanni et al, 2005a,b).…”

Section: Introductionmentioning

confidence: 99%

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53 Ϫ/Ϫ versus wild-type mice. p53 Ϫ/Ϫ spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53 Ϫ/Ϫ mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 Ϫ/Ϫ mice, while, similarly, p53 expression in p53 Ϫ/Ϫ cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

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“…spinal cord, such as phosphodiesterase 4, nestin, glia-derived neurite promoting factor and growth associated protein 43, were found to increase significantly in a higher level and earlier stage in the distal segment than in the injury site (Carmel et al, 2001;Grossman et al, 2001). T11 section is much closer to the injured site, so regeneration response here should occur later than L2 section.…”

Section: Discussionmentioning

confidence: 92%

“…It is well-known that changes in gene expression in the neurons distal to the injury site could reflect not only the regeneration response but also inflammatory and neuroprotective responses by diffusible signals from the injury site or by loss of synaptic input. In recent years, many investigators have observed the characteristic inflammatory response that emerged robustly at the injury site and spread to the distal cord in a lower level (Carmel et al, 2001;Aimone et al, 2004;De Biase et al, 2005). L2 section is farther from the transected section (between T9 and T10) than the T11 one.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of scirr1, a novel gene up-regulated after spinal cord injury

Liu¹,

Ma²,

Que³

et al. 2007

Exp Mol Med

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Spinal cord injury and regeneration involves transcriptional activity of many genes, of which many remain unknown. Using the rat spinal cord fulltransection model, bioinformatics, cloning, expression assays, fusion proteins, and transfection techniques, we identified and characterized one such differentially expressed gene, termed scirr1 (spinal cord injury and/or regeneration related gene 1). Fourteen orthologs were found in 13 species from echinoderm to insect and human by Blast search of NCBI protein reference sequence database. However, no further information is available for these homologues. Using whole-mount in situ hybridization, mouse scirr1 mRNA was expressed temporally and spatially in accordance with the early development sequence of the central nervous system. In adult rat spinal cord, expression of scirr1 mRNA was localized to neurons of gray matter by in situ hybridization. Using immunohistochemistry, SCIRR1 protein was found to be up-regulated and expressed more highly in spinal cord neurons farther from the epicenter of injury. Although the precise function of SCIRR1 is unknown, its unique pattern of expression during CNS early development and up-regulation after spinal cord injury suggest that SCIRR1 should be involved in the succeeding injury and/or repair processes of the injured spinal cord. Also, the typical F-box and leucine-rich repeat (LRR) architecture of rat SCIRR1 indicated that it may play an important substrate recruiting role in the pleiotropic ubiquitin/ proteasome pathway. All these make scirr1 a new interesting start to study the spinal cord injury and regeneration mechanism.

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Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss

Cited by 141 publications

References 53 publications

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

Identification and characterization of scirr1, a novel gene up-regulated after spinal cord injury

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