Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention

Hayta, Emrullah; Elden, Hasan

doi:10.1016/j.jchemneu.2017.08.001

Cited by 100 publications

(66 citation statements)

References 83 publications

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“…Given that the permeability of the blood-spinal cord-barrier (BSCB) increased significantly at the lesion site at 1 and 3 days post-SCI, fell greatly by 1 week post-SCI, and remained stable at uninjured sites [65], the ability of MSCs or exosomes to pass through the BSCB may be higher at injection time points within 1-week-post-SCI. Additionally, the inflammatory response develops within hours after SCI [66]; therefore, in this study, the first time point of intravenous-injection was chosen at 30 min post SCI to ensure that MSCs or MSC-exo exerted their functions at the beginning of the inflammatory cascade in spinal cord. Then the second injection was performed at 1 dpi to strengthen the effects.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

156

119

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Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

156

119

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“…However, the low number of cases receiving corticosteroids and the lack of randomization prevented us from attempting any direct comparison between the effect of these 2 classes of anti‐inflammatory drugs on the occurrence of UI or FI. The use of NSAIDs after SCI in humans has been reviewed . Overexpression of cyclooxygenase‐2 (COX2) in secondary injury after spinal cord trauma was demonstrated in a rat model, therefore opening a therapeutic window for COX2 inhibitors in SCI .…”

Section: Discussionmentioning

confidence: 99%

Predictors of urinary or fecal incontinence in dogs with thoracolumbar acute non‐compressive nucleus pulposus extrusion

Mari

Behr

Shea

et al. 2019

Veterinary Internal Medicne

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Background: Urinary (UI) and fecal (FI) incontinence occur in up to 7.5% and 32% of dogs, respectively, after thoracolumbar acute noncompressive nucleus pulposus extrusion (ANNPE).Hypotheses/Objectives: To investigate clinical, diagnostic, and therapeutic predictors of UI and FI in dogs with ANNPE affecting the T3-L3 spinal cord segments.Animals: Hundred and eighty-seven dogs with T3-L3 ANNPE diagnosed based on clinical and MRI findings.Methods: Multicenter retrospective study. Data were obtained from medical records and telephone questionnaires and analyzed by logistic regression.Results: UI and FI were reported in 17 (9.1%) and 44 (23.5%) dogs, respectively. Paraplegic dogs were 3 times (95% CI = 1.25, 10.87) more likely to develop UI (P = .018) and 4 times (95% CI = 1.94, 12.56) more likely to develop FI (P = .001) compared to nonparaplegic dogs. Dogs with an intramedullary hyperintensity greater than 40% of the cross-sectional area of the spinal cord at the same level on transverse T2-weighted MRI images were 4 times more likely to develop UI (95% CI = 1.04, 21.72; P = .045) and FI (95% CI = 1.56, 10.39; P = .004) compared to dogs with smaller lesions. FI was 3 times (95% CI = 1.41, 7.93) more likely in dogs that were not treated with nonsteroidal anti-inflammatory drugs (NSAIDs) after diagnosis compared to dogs administered NSAIDs (P = .006) and 2 times (95% CI = 1.12, 5.98) more likely in dogs presented with clinical signs compatible with spinal shock compared to dogs without (P = .026).Abbreviations: ANNPE, acute non-compressive nucleus pulposus extrusion; COX2, cyclooxygenase-2; FI, fecal incontinence; LL:VL, ratio of the length of the intramedullary lesion to the length of the L2 vertebra; NSAIDs, nonsteroidal anti-inflammatory drugs;PCSAL, percentage of the cross-sectional spinal cord area occupied by the lesion; SCI, spinal cord injury; UI, urinary incontinence.

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“…The development of SCI follows a distinct timeframe after the initial insult, and the timing of appropriate interventions is critical for effective therapy (Wilson et al 2012;Hayta and Elden 2018). One included study reported neuroprotection with riluzole administered at 1 h post SCI, which was superior to the neuroprotection achieved following treatment at 3 h after SCI .…”

Section: Timing Of Riluzole Administrationmentioning

confidence: 99%

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review

Zhou

Tian

Yao

et al. 2019

Journal of Neurochemistry

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Spinal cord injury (SCI) is a devastating condition that has few treatment options. Riluzole, a sodium channel blocker used to treat amyotrophic lateral sclerosis, has been initially trialed in human SCI. We performed a systematic review to critically assess the efficacy of riluzole in locomotor recovery and damage extension in SCI rat models, and the potential for clinical translation. PubMed, Embase, Cochrane Library, and Chinese databases were searched from their inception date to March 2018. Two reviewers independently selected animal studies that evaluated neurological recovery and lesion area following riluzole treatment in SCI rat models, extracted data and assessed methodological quality. Pairwise meta‐analysis, subgroup analysis, and network meta‐analysis were performed to assess the effects of riluzole on SCI. Ten eligible studies were included. Two studies had high methodological quality. Overall, the Basso, Beattie, and Bresnahan scores were increased in riluzole‐treated animals versus controls, and effect sizes showed a gradual increase from the 1st (five studies, n = 104, mean difference = 1.24, 95% CI = 0.11 to 2.37, p = 0.03) to 6th week after treatment (five studies, n = 120, mean difference = 2.34, 95% CI = 1.26 to 3.42, p < 0.0001). Riluzole was associated with improved outcomes in the inclined plane test and the tissue preservation area. Subgroup analyses suggested an association of locomotor recovery with riluzole dose. Network meta‐analysis showed that 5 mg/kg riluzole exhibited greater protection than 2.5 and 8 mg/kg riluzole. Collectively, this review suggests that riluzole has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials or applications. However, animal results should be interpreted with caution given the known limitations in animal experimental design and methodological quality.

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Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention

Cited by 100 publications

References 83 publications

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Predictors of urinary or fecal incontinence in dogs with thoracolumbar acute non‐compressive nucleus pulposus extrusion

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review

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