Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury

Dı́az-Ruiz, Araceli; Salgado–Ceballos, Hermelinda; Montes, Sergio; Guı́zar-Sahagún, Gabriel; Gelista-Herrera, Noemí; Méndez‐Armenta, Marisela; Dı́az-Cintra, Sofı́a; Rı́os, Camilo

doi:10.1002/jnr.22555

Cited by 29 publications

(30 citation statements)

References 45 publications

(44 reference statements)

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“…Likewise, dapsone enhanced the functional recovery and increased the amount of tissue preserved in animals with permanent brain ischemia [12]. Our group has also demonstrated its neuroprotective effect with better functional recovery in a rat SCI model [13]. Finally, we have also reported the anti-oxidant, neuroprotective and anticonvulsant effects of dapsone in a model of excitotoxic damage by kainic acid in rats [14].…”

Section: Introductionmentioning

confidence: 78%

“…It has also been demonstrated that dapsone suppresses intra-and extracellular production of superoxide in isolated human neutrophils [32]. The antioxidant effect of dapsone has been also shown indirectly by measuring lipid peroxidation both after ischemia with reperfusion, and SCI [10,13].…”

Section: Discussionmentioning

confidence: 96%

“…The anti-apoptotic effects of dapsone may be due to its ability to regulate upstream the key mechanisms of injury leading to cell death (excitotoxic damage, oxidative stress, and exacerbated inflammatory response) [10,13,14,25,41,42].…”

Section: Discussionmentioning

confidence: 99%

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Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats

et al. 2015

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Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti-apoptotic effect after SCI.

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 96%

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Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats

et al. 2015

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“…4 The secondary damage is characterized by ischemia, inflammation, glutamate excitotoxicity, oxidative stress and production of free radicals. 5 Soluble CD95L (sCD95L) is activated by cleavage of mCD95L by the serine matrix metalloproteinases MMP-7 and MMP-3. 6 sCD95L cannot trigger apoptosis, but induces the production of proinflammatory chemokine in neutrophils.…”

Section: Introductionmentioning

confidence: 99%

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

et al. 2012

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Study design: A pilot study measuring the levels of serum-soluble CD95 ligand (CD95L) in eight spinal cord-injured patients. Objectives: To determine the soluble concentration of CD95L in spinal cord injury (SCI) patients after trauma. Methods: We collected blood samples from eight patients with acute traumatic SCI. Soluble CD95L serum levels were determined using an enzyme-linked immunosorbent assay. American Spinal Injury Association (ASIA) was determined according to ASIA classification. The patients were monitored, and venous blood was drawn after arrival at the hospital on the 1st and 3rd day and during the 1st, 2nd, 4th, 8th and 12th weeks after trauma. Results: The average patient age was 48.1 years (18-86 years). Three patients were paraplegic (two incomplete, one complete), five were quadriplegic (one complete, four incomplete). The serum concentration of soluble CD95L (sCD95L) decreased during the 1st week (41 ng l À1 ) and increased after the 2nd week in all eight patients. It peaked during the 4th week (68.5 ng l À1 ) and reached a plateau during the 12th week (76.2 ng l À1 ). There are many possible explanations for not being able to detect a statistical significance, one of course being the small sample size. Conclusion: Promising results for anti-CD95L therapy have already been documented in lab studies with rodents. Anti-CD95L blocks the pro-apoptotic and proinflammatory activity of membrane-bound CD95L during the acute phase of SCI. We observed that sCD95L levels are elevated during the subacute and intermediate phases of SCI. It would be of great interest to study a larger group of patients to determine whether higher sCD95 levels are correlated with improved or impaired neurological outcome or with increasing levels of autoimmune components in peripheral blood.

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“…MPO activity was measured as previously described [35]. Briefly, tissues were homogenized in ice-cold phosphate buffer (PB).…”

Section: Methodsmentioning

confidence: 99%

Creation of an intramedullary cavity by hemorrhagic necrosis removal 24 h after spinal cord contusion in rats for eventual intralesional implantation of restorative materials

Guı́zar-Sahagún

Martínez-Cruz²,

Franco-Bourland

et al. 2017

PLoS ONE

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Intramedullary hemorrhagic necrosis occurs early after spinal cord injury at the site of injury and adjacent segments. It is considered harmful because of its potential to aggravate secondary injury, and to interfere with axonal regeneration; it might also lead to an unfavorable environment for intralesional implants. Removal of hemorrhagic necrosis has been attempted before with variable results. The invasive nature of these procedures carries the risk of exacerbating damage to the injured cord. The overall objective for this study was to test several strategies for non-damaging removal of hemorrhagic necrosis and characterize the resulting cavity looking for a space for future intralesional therapeutic implants in rats with acute cord injury. Rats were subjected to graded cord contusion, and hemorrhagic necrosis was removed after 24h. Three grades of myelotomy (extensive, medium sized, and small) were tested. Using the small surgical approach to debridement, early and late effects of the intervention were determined by histology and by analytical and behavioral analysis. Appearance and capacity of the resulting cavity were characterized. Satisfactory removal of hemorrhagic necrosis was achieved with all three surgical approaches to debridement. However, bleeding in spared cord tissue was excessive after medium sized and extensive myelotomies but similar to control injured rats after small cord surgery. Small surgical approach to debridement produced no swelling nor acute inflammation changes, nor did it affect long-term spontaneous locomotor recovery, but resulted in modest improvement of myelination in rats subjected to both moderate and severe injuries. Cavity created after intervention was filled with 10 to 15 μL of hydrogel. In conclusion, by small surgical approach to debridement, removal of hemorrhagic necrosis was achieved after acute cord contusion thereby creating intramedullary spaces without further damaging the injured spinal cord. Resulting cavities appear suitable for future intralesional placement of pro-reparative cells or other regenerative biomaterials in a clinically relevant model of spinal cord injury.

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Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury

Cited by 29 publications

References 45 publications

Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats

Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

Creation of an intramedullary cavity by hemorrhagic necrosis removal 24 h after spinal cord contusion in rats for eventual intralesional implantation of restorative materials

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