Enhanced Oligodendrocyte Survival after Spinal Cord Injury in Bax-Deficient Mice and Mice with Delayed Wallerian Degeneration

Dong, Hongxin; Fazzaro, Alicia; Xiang, Chuanxi; Korsmeyer, Stanley J.; Jacquin, Mark F.; McDonald, John W.

doi:10.1523/jneurosci.23-25-08682.2003

Cited by 103 publications

(73 citation statements)

References 61 publications

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“…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]. Moreover, the proinflammatory cytokines induce other biochemical signals leading to the degeneration of myelin and apoptosis of neurons that cause the neurological deficit [46,47]. Herein, we show that inhibition of proinflammatory cytokines is detected in GILZ TG , including the production of TNF-α and IL-1β, which are crucial factors for inflammation development [4,7,35].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Oligodendrocyte death is a prominent feature of the secondary degeneration after SCI (Lu et al, 2000;Blight, 2002;Dong et al, 2003;Park et al, 2004). Several lines of evidence have suggested that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed post traumatic spinal cord white matter degeneration (Faden and Simon, 1988;Wrathall et al, 1994;Agrawal and Fehlings, 1997;Wrathall et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…These processes are mediated by changes in the constitution of a variety of extracellular matrix components (Sanes, 1983(Sanes, , 1989, growth factors (Mocchetti and Wrathall, 1995), and proteolytic cascades (Krystosek and Seeds, 1981;Monard, 1988;Seeds et al, 1990). Several groups have now demonstrated that oligodendrocyte death and subsequent demyelination are involved in the pathology after SCI (Lu et al, 2000;Blight, 2002;Dong et al, 2003;Park et al, 2004). Oligodendrocyte loss and demyelination result in inadequate nerve conduction and the appearance of neurological deficits, which are potential targets for improving function after SCI even in the absence of axonal regeneration.…”

Section: Introductionmentioning

confidence: 99%

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

et al. 2007

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Abbreviations: SCI, spinal cord injury; DIG, digoxigenin; APC, adenomatus polyposis coli; MBP, myelin basic protein; TUNEL, TdT-mediated dUTP-fluorescein nick end labeling -3 - AbstractPrevious studies indicated that the expression of neuropsin, a serine protease, is induced in mature oligodendrocytes after injury to the central nervous system (CNS). The pathophysiology of spinal cord injury (SCI) involves primary and secondary mechanisms, the latter contributing further to permanent losses of function. To explore the role of neuropsin after SCI, histochemical and behavioral analyses were performed in wild-type (WT) and neuropsin-deficient (neuropsin -/-) mice using a crush injury model, a well-characterized and consistently reproducible model of SCI. In situ hybridization revealed that neuropsin mRNA expression was induced in the spinal cord white matter from WT mice after crush SCI, peaking at day 4. Neuropsin -/-mice showed attenuated demyelination, oligodendrocyte death, and axonal damage after SCI.Although axonal degeneration in the corticospinal tract was obvious caudal to the lesion site in both strains of mice after SCI, the number of surviving nerve fibers caudal to the lesion was significantly larger in neuropsin -/-mice than WT mice. Behavioral analysis revealed that the recovery at days 10-42 was significantly improved in neuropsin -/-mice compared to WT mice in spite of the severe initial hindlimb impairments due to SCI in both strains. These observations suggest that neuropsin is involved in the secondary phase of the pathogenesis of SCI mediated by demyelination, oligodendrocyte death, and axonal degeneration.-4 -

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“…Also, our data do not exclude the possibility that apoptotic mechanisms play key roles in the death of non-neuronal cells in CNS trauma. For example, in SCI, neurological dysfunction is attrib- utable in part to oligodendrocyte apoptosis (Beattie et al, 2002;Dong et al, 2003;Stirling et al, 2004). Rather, our focus here was on mechanisms that can lead to neuronal damage in mild in vitro stretch injury .…”

Section: Discussionmentioning

confidence: 99%

Vulnerability of Central Neurons to Secondary Insults afterIn VitroMechanical Stretch

Arundine¹,

Aarts²,

Lau³

et al. 2004

J. Neurosci.

119

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Mild traumatic brain injuries are of major public health significance. Neurons in such injuries often survive the primary mechanical deformation only to succumb to subsequent insults. To study mechanisms of vulnerability of injured neurons to secondary insults, we used an in vitro model of sublethal mechanical stretch. Stretch enhanced the vulnerability of the neurons to excitotoxic insults, causing nuclear irregularities, DNA fragmentation, and death suggestive of apoptosis. However, the DNA degradation was not attributable to classical (caspase mediated) or caspase-independent apoptosis. Rather, it was associated with profound stretch-induced mitochondrial dysfunction and the overproduction of reactive oxygen species (ROS). Sublethally stretched neurons produced surprisingly high levels of ROS, but these in isolation were insufficient to kill the cells. To be lethal, the ROS also needed to combine with nitric oxide (NO) to form the highly reactive species peroxynitrite. Peroxynitrite was not produced after stretch alone and arose only after combining stretch with an insult capable of stimulating NO production, such as NMDA or an NO donor. This explained the exquisite sensitivity of sublethally stretched neurons to a secondary NMDA insult. ROS scavengers and NO synthase (NOS) inhibitors prevented cell death and DNA degradation. Moreover, inhibiting neuronal NOS activation by NMDA using peptides that perturb NMDA receptor-postsynaptic density-95 interactions also reduced protein nitration and cell death, indicating that the reactive nitrogen species produced were neuronal in origin. Our data explain the mechanism of enhanced vulnerability of sublethally injured neurons to secondary excitotoxic insults and highlight the importance of secondary mechanisms to the ultimate outcome of neurons in mild neurotrauma.

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Enhanced Oligodendrocyte Survival after Spinal Cord Injury in Bax-Deficient Mice and Mice with Delayed Wallerian Degeneration

Cited by 103 publications

References 61 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

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

Vulnerability of Central Neurons to Secondary Insults afterIn VitroMechanical Stretch

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