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Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice.

ABSTRACT: Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia.Mice were subjected to spinal cord ischemia induced by occlusion of the aortic arch and left subclavian artery for 5 or 9 minutes. Motor function in the hind limb was evaluated up to 72 hours after spinal cord ischemia. Histological studies were performed to detect caspase-3 activation, glial activation, and motor neuron survival in the serial spinal cord sections. To investigate the impact of caspase-3 activation on spinal cord ischemia, outcome of the spinal cord ischemia was examined in mice deficient for caspase-3.In wild-type mice, 9 minutes of spinal cord ischemia caused immediate paraplegia, whereas 5 minutes of ischemia caused delayed paraplegia. Delayed paraplegia after 5 minutes of spinal cord ischemia was associated with histological evidence of caspase-3 activation, reactive astrogliosis, microglial activation, and motor neuron loss starting at approximately 24 to 48 hours after spinal cord ischemia. Caspase-3 deficiency prevented delayed paraplegia and motor neuron loss after 5 minutes of spinal cord ischemia, but not immediate paraplegia after 9 minutes of ischemia.The present results suggest that caspase-3 activation is required for delayed paraplegia and motor neuron degeneration after spinal cord ischemia.

SUBMITTER: Kakinohana M

PROVIDER: S-EPMC3199137 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice.

Kakinohana Manabu M Kida Kotaro K Minamishima Shizuka S Atochin Dmitriy N DN Huang Paul L PL Kaneki Masao M Ichinose Fumito F

Stroke 20110623 8

<h4>Background and purpose</h4>Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia.<h4>Methods</h4>Mice were subjected to spi ...[more]

PMID: 21700940

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Project description:BackgroundDelayed paraplegia is a devastating complication of thoracoabdominal aortic surgery. Hydrogen sulfide (H2S) was reported to be protective in a mouse model of spinal cord ischemia and the beneficial effect of H2S has been attributed to polysulfides. The objective of this study was to investigate the effects of polysulfides on delayed paraplegia after spinal cord ischemia.Methods and resultsSpinal cord ischemia was induced in male and female C57BL/6J mice by clamping the aortic arch and the left subclavian artery. Glutathione trisulfide (GSSSG), glutathione (GSH), glutathione disulfide (GSSG), or vehicle alone was administered intranasally at 0, 8, 23, and 32 h after surgery. All mice treated with vehicle alone developed paraplegia within 48 h after surgery. GSSSG, but not GSH or GSSG, prevented paraplegia in 8 of 11 male mice (73%) and 6 of 8 female mice (75%). Intranasal administration of 34S-labeled GSSSG rapidly increased 34S-labeled sulfane sulfur species in the lumbar spinal cord. In mice treated with intranasal GSSSG, there were increased sulfane sulfur levels, and decreased neurodegeneration, microglia activation, and caspase-3 activation in the lumbar spinal cord. In vitro studies using murine primary cortical neurons showed that GSSSG increased intracellular levels of sulfane sulfur. GSSSG, but not GSH or GSSG, dose-dependently improved cell viability after oxygen and glucose deprivation/reoxygenation (OGD/R). Pantethine trisulfide (PTN-SSS) also increased intracellular sulfane sulfur and improved cell viability after OGD/R. Intranasal administration of PTN-SSS, but not pantethine, prevented paraplegia in 6 of 9 male mice (66%).ConclusionsIntranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases.

Project description:BackgroundSpinal cord ischemic injury is a severe complication of aortic surgery. We hypothesized that cerebrospinal fluid (CSF) oxygenation with nanobubbles after reperfusion could ameliorate spinal cord ischemic injury.MethodsTwenty white Japanese rabbits were categorized into 4 groups of 5 rabbits each: sham group, with balloon catheter insertion into the aorta; ischemia group, with spinal cord ischemic injury by abdominal aortic occlusion; nonoxygenated group, with nonoxygenated artificial CSF irrigation after spinal cord ischemic injury; and oxygenated group, with oxygenated artificial CSF irrigation after spinal cord ischemic injury. At 48 hours after spinal cord ischemic injury, the modified Tarlov score to reflect hind limb movement was evaluated. The spinal cord was histopathologically examined by counting anterior horn cells, and microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses were performed.ResultsThe oxygenated group showed improved neurologic function compared with the ischemia and nonoxygenated groups (P < .01 and P = .019, respectively). Anterior horn neuron prevention in the sham, nonoxygenated, and oxygenated groups was confirmed (mean modified Tarlov score: sham, 9.2 ± 1.9; nonoxygenated, 10.2 ± 2.2; oxygenated, 10.4 ± 2.2; ischemia, 2.7 ± 2.7). Microarray analysis identified 644 genes with twofold or greater increased signals between the ischemia and sham groups. Thirty-three genes related to inflammatory response were enriched among genes differentially expressed between the oxygenated and ischemia groups. Interleukin (IL)-6 and tumor necrosis factor (TNF) expression levels were significantly lower in the oxygenated group compared with the ischemia group, while qRT-PCR showed lower IL-6 and TNF expression levels in the oxygenated group compared with the ischemia group (P < .05).ConclusionsCSF oxygenation with nanobubbles after reperfusion can ameliorate spinal cord ischemic injury and suppress inflammatory responses in the spinal cord.

Project description:BackgroundIschemic spinal cord injury (SCI) belongs to the heterogeneous group of non-traumatic SCI, while the course of sensorimotor and functional recovery is comparable to traumatic SCI. Recently, we derived from data of patients with traumatic SCI a valid model to predict an independent and reliable bowel management one year after SCI.AimTo evaluate the performance of this model to predict an independent and reliable bowel management one year following ischemic SCI.DesignPrognostic study - observational study.SettingEuropean Multicenter Study about Spinal Cord Injury (EMSCI) ClinicalTrials.gov: NCT01571531.PopulationOne hundred and forty-two patients with ischemic SCI of various level and severity of injury.MethodsThe prediction model relied on a single predictor collected within 40 days from injury, the International Standards for Neurological Classification of Spinal Cord Injury total motor score. Bowel outcome one year after SCI derived from the dichotomization of the Spinal Cord Independence Measure (SCIM) item 7 scores. We defined a positive outcome as independent bowel management with regular movements and appropriate timing with no or rare accidents (score of 10 in SCIM version II and score of 8 or 10 in version III).ResultsThe model showed a fair discrimination with an area under the receiver operating characteristic (ROC) curve of 0.780 (95% confidence interval=0.702-0.860). In addition, the model displayed an acceptable accuracy and calibration.ConclusionsThe study extends the validity of our rule to patients with ischemic SCI, thus providing the first model to predict an independent and reliable bowel management in this population.Clinical rehabilitation impactThe model may be employed in clinical practice to counsel patients, to define the rehabilitation aims and to estimate the need of assistance after discharge, as well as in the research field for the optimization of patients' allocation in the design of future clinical trials.

Project description:BackgroundNafamostat mesylate (nafamostat, NM) is an FDA-approved serine protease inhibitor that exerts anti-neuroinflammation and neuroprotective effects following rat spinal cord injury (SCI). However, clinical translation of nafamostat has been limited by an unclear administration time window and mechanism of action.MethodsTime to first dose of nafamostat administration was tested on rats after contusive SCI. The optimal time window of nafamostat was screened by evaluating hindlimb locomotion and electrophysiology. As nafamostat is a serine protease inhibitor known to target thrombin, we used argatroban (Arg), a thrombin-specific inhibitor, as a positive control in the time window experiments. Western blot and immunofluorescence of thrombin expression level and its enzymatic activity were assayed at different time points, as well its receptor, the protease activated receptor 1 (PAR1) and downstream protein matrix metalloproteinase-9 (MMP9). Blood-spinal cord barrier (BSCB) permeability leakage indicator Evans Blue and fibrinogen were analyzed along these time points. The infiltration of peripheral inflammatory cell was observed by immunofluorescence.ResultsThe optimal administration time window of nafamostat was 2-12 h post-injury. Argatroban, the thrombin-specific inhibitor, had a similar pattern. Thrombin expression peaked at 12 h and returned to normal level at 7 days post-SCI. PAR1, the thrombin receptor, and MMP9 were significantly upregulated after SCI. The most significant increase of thrombin expression was detected in vascular endothelial cells (ECs). Nafamostat and argatroban significantly downregulated thrombin and MMP9 expression as well as thrombin activity in the spinal cord. Nafamostat inhibited thrombin enrichment in endothelial cells. Nafamostat administration at 2-12 h after SCI inhibited the leakage of Evans Blue in the epicenter and upregulated tight junction proteins (TJPs) expression. Nafamostat administration 8 h post-SCI effectively inhibited the infiltration of peripheral macrophages and neutrophils to the injury site.ConclusionsOur study provides preclinical information of nafamostat about the administration time window of 2-12 h post-injury in contusive SCI. We revealed that nafamostat functions through inhibiting the thrombin-mediated BSCB breakdown and subsequent peripheral immune cells infiltration.

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Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice.

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Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice.

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