Prostaglandin release by spinal cord injury mediates production of hydroxyl radical, malondialdehyde and cell death: a site of the neuroprotective action of methylprednisolone

Abstract During the progression of the neurodegenerative process, mitochondria participates in several intercellular signaling pathways. Voltage-dependent anion-selective channel 1 (VDAC1) is a mitochondrial porin involved in the cellular metabolism and apoptosis intrinsic pathway in many neuropathological processes. In spinal cord injury (SCI), after the primary cell death, a secondary response that comprises the release of pro-inflammatory molecules triggers apoptosis, inflammation, and demyelination, often leading to the loss of motor functions. Here, we investigated the functional role of VDAC1 in the neurodegeneration triggered by SCI. We first determined that in vitro targeted ablation of VDAC1 by specific morpholino antisense nucleotides (MOs) clearly promotes neurite retraction, whereas a pharmacological blocker of VDAC1 oligomerization (4, 4′-diisothiocyanatostilbene-2, 2′-disulfonic acid, DIDS), does not cause this effect. We next determined that, after SCI, VDAC1 undergoes conformational changes, including oligomerization and N-terminal exposition, which are important steps in the triggering of apoptotic signaling. Considering this, we investigated the effects of DIDS in vivo application after SCI. Interestingly, blockade of VDAC1 oligomerization decreases the number of apoptotic cells without interfering in the neuroinflammatory response. DIDS attenuates the massive oligodendrocyte cell death, subserving undisputable motor function recovery. Taken together, our results suggest that the prevention of VDAC1 oligomerization might be beneficial for the clinical treatment of SCI.

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Acute upregulation of bone morphogenetic protein-4 regulates endogenous cell response and promotes cell death in spinal cord injury

Experimental Neurology ◽

10.1016/j.expneurol.2019.113163 ◽

2020 ◽

Vol 325 ◽

pp. 113163 ◽

Cited By ~ 1

Author(s):

Christopher G. Hart ◽

Scott M. Dyck ◽

Hardeep Kataria ◽

Arsalan Alizadeh ◽

Pandian Nagakannan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Bone Morphogenetic Protein ◽

Cell Response ◽

Bone Morphogenetic Protein 4 ◽

Morphogenetic Protein ◽

Cord Injury

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Cell Death in Spinal Cord Injury (SCI) Requires de Novo Protein Synthesis

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2001.tb03655.x ◽

2006 ◽

Vol 939 (1) ◽

pp. 436-449 ◽

Cited By ~ 30

Author(s):

SWAPAN K. RAY ◽

DENISE D. MATZELLE ◽

GLORIA G. WILFORD ◽

EDWARD L. HOGAN ◽

NAREN L. BANIK

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Protein Synthesis ◽

De Novo ◽

Cord Injury ◽

De Novo Protein Synthesis

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Chronic thoracic spinal cord injury impairs CD8+ T-cell function by up-regulating programmed cell death-1 expression

Journal of Neuroinflammation ◽

10.1186/1742-2094-11-65 ◽

2014 ◽

Vol 11 (1) ◽

pp. 65 ◽

Cited By ~ 17

Author(s):

Ji Zha ◽

Annalise Smith ◽

Samita Andreansky ◽

Valerie Bracchi-Ricard ◽

John R Bethea

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Programmed Cell Death ◽

Cell Function ◽

Cd8 T Cell ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Programmed Cell Death 1 ◽

Cord Injury

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Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury

Journal of Neurosurgery Spine ◽

10.3171/spi.2005.2.3.0327 ◽

2005 ◽

Vol 2 (3) ◽

pp. 327-334 ◽

Cited By ~ 34

Author(s):

Ahmet Çolak ◽

Alper Karaoǧlan ◽

Şeref Barut ◽

Sibel Köktürk ◽

Aysşenur Iǧdem Akyildiz ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Rat Model ◽

Caspase 9 ◽

Content Type ◽

Cord Injury ◽

Group 3 ◽

Group 2 ◽

Fine Print

Object. Apoptosis is considered one of the most significant mechanisms in the pathogenesis of neuronal damage after spinal cord injury (SCI). This form of cell death occurs via mediators known as caspases. The aim of this study was to evaluate the neuroprotective effect of the caspase-9 inhibitor, z-LEHD-fmk, in a rat model of spinal cord trauma. Methods. Fifty-four Wistar albino rats were studied in the following three groups of 18 animals each: sham-operated controls (Group 1); trauma-only controls (Group 2); and trauma combined with z-LEHD-fmk—treated animals (0.8 µM/kg; Group 3). Spinal cord injury was produced at the thoracic level by using the weight-drop technique. Responses to SCI and the efficacy of z-LEHD-fmk treatment were determined on the basis of terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick—end labeling staining and light and electron microscopy findings in cord tissue at 24 hours and 7 days posttrauma. Six rats from each group were also assessed for functional recovery at 3 and 7 days after SCI. This was conducted using the inclined-plane technique and a modified version of the Tarlov motor grading scale. At 24 hours postinjury, light microscopic examination of Group 2 tissue samples showed hemorrhage, edema, necrosis, polymorphonuclear leukocyte infiltration, and vascular thrombi. Those obtained in Group 3 rats at this stage showed similar features. At 24 hours postinjury, the mean apoptotic cell count in Group 2 was significantly higher than that in Group 3 (90.25 ± 2.6 and 50.5 ± 1.9, respectively; p < 0.05). At 7 days postinjury, the corresponding mean apoptotic cell counts were 49 ± 2.1 and 17.7 ± 2.6, also a significant difference (p < 0.05). Electron microscopy findings confirmed the occurrence of programmed cell death in different cell types in the spinal cord and showed that z-LEHD-fmk treatment protected neurons, glia, myelin, axons, and intracellular organelles. Conclusions. Examination of the findings in this rat model of SCI revealed that apoptosis occurs not only in neurons and astrocytes but also in oligodendrocytes and microglia. Furthermore, immediate treatment with the caspase-9 inhibitor z-LEHD-fmk blocked apoptosis effectively and was associated with better functional outcome. More in-depth research of the role of programmed cell death in spinal cord trauma and further study of the ways in which caspases are involved in this process may lead to new strategies for treating SCI.

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