Clinical Trials in Traumatic Spinal Cord Injury

Donovan, Jayne; Kirshblum, Steven

doi:10.1007/s13311-018-0632-5

Cited by 79 publications

(58 citation statements)

References 170 publications

(167 reference statements)

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“…In SCI, after the initial mechanical damages, other pathophysiologic mechanisms occur in the spinal cord, including inflammation, oxidative stress, edema, and mitochondrial dysfunction (Quadri et al, 2018), which work toward post-SCI tissue and functional reconstruction (Hausmann, 2003). Unfortunately, there is currently no effective therapeutic strategy in clinical practice for SCI; further, the regulatory molecular mechanisms underlying SCI remain unclear (Donovan and Kirshblum, 2018).…”

Section: Introductionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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Spinal cord injury (SCI) is a serious condition that affects bodily function; however, there is no effective therapy in clinical practice. MCC950, a selective NOD-like receptor protein-3 (NLRP3) inflammasome inhibitor, has been reported to alleviate canonical and non-canonical NLRP3 inflammasome activation of the inflammatory response in vitro and in vivo. However, the effect of MCC950 treatment on neurological post-SCI recovery remains unclear. In this study, we assessed the pharmacological effect of MCC950 on an experimental SCI model in vivo and neuronal injury in vitro. We found that MCC950 improved the grip strength, hind limb movements, spinal cord edema, and pathological injury in the SCI mice. We demonstrated that it exerted this effect by blocking NLRP3 inflammasome assembly, including NLRP3-ASC and NLRP3-Caspase-1 complexes, as well as the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-18. Moreover, we found that MCC950 reduced spinal neuron injury and NLRP3 inflammasome activation, which had been induced by oxygen-glucose deprivation (OGD) or lipopolysaccharides (LPS) in vitro. In conclusion, our findings indicate that MCC950 alleviates inflammatory response and improves functional recovery in the acute mice model of SCI by blocking NLRP3 inflammasome assembly and alleviating downstream neuroinflammation. Therefore, these findings could prove useful in the development of effective therapeutic strategies for the treatment and prognosis of SCI.

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Section: Introductionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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“…[1][2][3] Primary injury, resulting from the extraneous mechanical force impacting directly on the spinal cord, is characterized by focal cellular, vascular and blood-spinal cord barrier injury; the primary injury of SCI is irreversible. 5 Therefore targeted therapies for inflammation in the secondary injury of SCI are still lacking. The major events in the phase of secondary injury of SCI including oedema, ischaemia, inflammation, cell death and scar forming, among which inflammation is considered to be a major target for secondary injury.…”

Section: Introductionmentioning

confidence: 99%

“…2,4 Methylprednisolone is a corticosteroid thought to inhibit the inflammatory cascade contributing to secondary injury in SCI and it is the only drug that was recommended for SCI therapy; however later studies found methylprednisolone to be controversial for its efficacy and potential complications. 5 Therefore targeted therapies for inflammation in the secondary injury of SCI are still lacking.…”

Section: Introductionmentioning

confidence: 99%

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats

Wang

Chen

Jin

et al. 2019

J Cellular Molecular Medi

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The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. For the irreversibility of primary injury, therapies of SCI mainly focus on secondary injury, whereas inflammation is considered to be a major target for secondary injury; however the regulation of inflammation in SCI is unclear and targeted therapies are still lacking. In this study, we found that the expression of BRD4 was correlated with pro‐inflammatory cytokines after SCI in rats; in vitro study in microglia showed that BRD4 inhibition either by lentivirus or JQ1 may both suppress the MAPK and NF‐κB signalling pathways, which are the two major signalling pathways involved in inflammatory response in microglia. BRD4 inhibition by JQ1 not only blocked microglial M1 polarization, but also repressed the level of pro‐inflammatory cytokines in microglia in vitro and in vivo. Furthermore, BRD4 inhibition by JQ1 can improve functional recovery and structural disorder as well as reduce neuron loss in SCI rats. Overall, this study illustrates that microglial BRD4 level is increased after SCI and BRD4 inhibition is able to suppress M1 polarization and pro‐inflammatory cytokine production in microglia which ultimately promotes functional recovery after SCI.

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“…Traumatic spinal cord injury (SCI), a catastrophic and disabling disease, mainly results from external physical impacts such as traffic accidents, sports, falls and accident at work (primary injury), followed with the secondary injury [1] . The primary injury is usually temporary and irreversible [2] while the secondary injury causes the permanent neurological deficits primarily including motor and sensory dysfunction [1,3] . The direct damage to spinal cord cells initiates the complicated and devastating secondary injury cascade which may contribute to the permanent function impairment [4] and psychological debilitation [5] .…”

Section: Introductionmentioning

confidence: 99%

Activation of SIRT1 by Hyperbaric Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

Chen¹,

Yao²,

Li³

et al. 2020

Preprint

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Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

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Clinical Trials in Traumatic Spinal Cord Injury

Cited by 79 publications

References 170 publications

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats

Activation of SIRT1 by Hyperbaric Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

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