Molecular insights of the injured lesions of rat spinal cords: Inflammation, apoptosis, and cell survival

Ahn, Young Hwan; Lee, Gwang; Kang, Seok Kwon

doi:10.1016/j.bbrc.2006.07.105

Cited by 59 publications

(32 citation statements)

References 35 publications

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“…Previously, it has been shown that between 12 h and 72 h after experimental SCI induction, gene expression of proinflammatory cytokines and their receptors, including IL-1β, TNF-α, and IL-10, is significantly increased [41][42][43][44]. This indicates the importance of the role of soluble factors in mediating the inflammatory process, including the recruitment of inflammatory cells into the injury site [45].…”

Section: Discussionmentioning

confidence: 94%

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

et al. 2012

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Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent antiinflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoidinduced leucine zipper (GILZ) transgenic (GILZ TG ) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ TG were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ TG as compared to wild-type mice. Moreover, GILZ TG showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI.

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Section: Discussionmentioning

confidence: 94%

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

et al. 2012

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“…Detailed discussion of these changes is beyond the scope of this review, and the reader is directed to several excellent reviews on the pathophysiological changes occurring in the spinal cord following injury [6][7][8][9]. However, of particular interest for this discussion are the ionic shifts that occur in the injured tissue that persist for hours and days following SCI [10][11][12][13].…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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“…Necrosis initiates inflammatory responses via activation of microglia and macrophages, which then release soluble factors, including nitric oxide, free radicals, proteolytic enzymes, arachidonic acid metabolites, tumor necrosis factor, interleukin-1, cyclooxygenase-2 and prostaglandins (Schnell et al, 1999;Popovich et al, 2002;Beattie, 2004;Ahn et al, 2006). A large body of evidence suggests that all these inflammatory agents released by microglia can stimulate neuronal death (Beattie, 2004;Skaper et al, 2006;Gibbons and Dragunow, 2006), and in turn, promote further microglial activation (Gomes-Leal et al, 2004).…”

Section: Tat-bcl-x L and Tat-bh4 Increased Neuronal Loss And Microglimentioning

confidence: 99%

“…Mechanical trauma to the spinal cord triggers events resulting in the death of neurons and glia over several weeks after the initial injury (Liu et al, 1997;Ahn et al, 2006). In the early acute phase, there is a cascade of excitatory amino-acid-induced Ca 2+ entry and energy failure, nitric oxide (NO) production, oxidative stress and membrane breakdown that lead to early necrosis (Park et al, 2004;Bao and Liu, 2004;Bao et al, 2006), which is followed by apoptosis of neurons and glia (Beattie et al, 2000;Lu et al, 2000;Park et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Detrimental effects of antiapoptotic treatments in spinal cord injury

Cittelly¹,

Nešić²,

Johnson³

et al. 2008

Experimental Neurology

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Long term functional impairments due to spinal cord injury (SCI) in the rat result from secondary apoptotic death regulated, in part, by SCI-induced decreases in protein levels of the anti-apoptotic protein Bcl-x L . We have shown that exogenous administration of Bcl-x L spares neurons 24h after SCI. However, long term effects of chronic application of Bcl-x L have not been characterized. To counteract SCI-induced decreases in Bcl-x L and resulting apoptosis, we used the TAT protein transduction domain fused to the Bcl-x L protein (Tat-Bcl-x L ), or its anti-apoptotic domain BH4 (Tat-BH4). We used intrathecal delivery of Tat-Bcl-x L , or Tat-BH4, into injured spinal cords for 24h or 7 days, and apoptosis, neuronal death and locomotor recovery were assessed up to 2 months after injury. Both, Tat-Bcl-x L and Tat-BH4, significantly decreased SCI-induced apoptosis in thoracic segments containing the site of injury (T10) at 24h or 7 days after SCI. However, the 7 day delivery of Tat-Bcl-x L , or Tat-BH4, also induced a significant impairment of locomotor recovery that lasted beyond the drug delivery time. We found that the 7 day administration of TatBcl-x L , or Tat-BH4, significantly increased non-apoptotic neuronal loss and robustly augmented microglia/macrophage activation. These results indicate that the anti-apoptotic treatment targeting Bcl-x L shifts neuronal apoptosis to necrosis, increases the inflammatory response and impairs locomotor recovery. Our results suggest that a combinatorial treatment consisting of anti-apoptotic and anti-inflammatory agents may be necessary to achieve tissue preservation and significant improvement in functional recovery after SCI.

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Molecular insights of the injured lesions of rat spinal cords: Inflammation, apoptosis, and cell survival

Cited by 59 publications

References 35 publications

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Detrimental effects of antiapoptotic treatments in spinal cord injury

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