Global burden of traumatic brain and spinal cord injury

Badhiwala, Jetan H.; Wilson, Jefferson R.; Fehlings, Michael G.

doi:10.1016/s1474-4422(18)30444-7

Cited by 189 publications

(126 citation statements)

References 8 publications

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“…Spinal cord injury (SCI) is one of the most destructive neurological traumas and typically results from vehicle accidents, falls and violence. SCI is characterized by impaired sensory and motor function, which in some instances can be life-threatening, resulting in great challenges associated with health-related quality of life and lifetime healthcare costs ( Badhiwala et al, 2019 ; Courtine and Sofroniew, 2019 ). The physiological progression of SCI involves two phases, the primary injury, which is caused by an immediate mechanical insult, then the secondary injury, which arises following the initial damage that triggers a series of molecular events, including the inflammatory response, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress and axonal demyelination, exacerbating the initial injury and affecting neural repair for a several weeks ( Silva et al, 2014 ; Brommer et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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“…As a most clinical spinal cord injuries are incomplete and at the cervical level, a reliable research model to serve as a basis for basic research studies and testing therapeutics is critical for progress in the field [21]. Further, previous unilateral cervical models in mice have been limited to a single severity with a floor effect on many behavioral tasks [6], diminishing the potential for recovery with therapeutic intervention.…”

Section: Plos Onementioning

confidence: 99%

The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury

et al. 2020

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There are approximately 1.2 million people currently living with spinal cord injury (SCI), with a majority of cases at the cervical level and half involving incomplete injuries. Yet, as most preclinical research has been focused on bilateral thoracic models, there remains a disconnect between bench and bedside that limits translational success. Here, we profile a clinically relevant model of unilateral cervical contusion injury in the mouse (30kD with 0, 2, 5, or 10 second dwell time). We demonstrate sustained behavioral deficits in performance on grip strength, cylinder reaching, horizontal ladderbeam and CatWalk automated gait analysis tasks. Beyond highlighting reliable parameters for injury assessment, we also explored the effect of mouse strain and age on injury outcome, including evaluation of constitutively immunodeficient mice relevant for neurotransplantation and cellular therapy testing. Comparison of C57Bl/6 and immunodeficient Rag2gamma(c)-/-as well as Agouti SCIDxRag2-Gamma(c)-/-hybrid mouse strains revealed fine differences in post-injury ipsilateral grip strength as well as total number of rearings on the cylinder task. Differences in post-SCI contralateral forepaw duty cycle and regularity index as measured by CatWalk gait analysis between the two immunodeficient strains were also observed. Further, assessment of young (3-4 months old) and aging (16-17 months old) Rag2gamma(c)-/-mice identified age-related pre-injury differences in strength and rearing that were largely masked following cervical contusion injury; observations that may help interpret previous results in aged rodents as well as human clinical trials. Collectively, the work provides useful insight for experimental design and analysis of future pre-clinical studies in a translational unilateral cervical contusion injury model.

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“…Acute traumatic spinal cord injury (SCI) is a devastating disorder that exerts a significant physical, emotional, and economic burden on patients, families, and society at large. 1,2 The pathophysiology of SCI involves primary and secondary injury mechanisms; the rationale for expeditious surgical decompression in the setting of acute SCI is that it may mitigate secondary injury, improving long-term neurological outcomes. 3,4 To this end, pre-clinical studies have demonstrated better neurobehavioral outcomes in rodent models of SCI when the time from injury to decompression is minimized.…”

Section: Introductionmentioning

confidence: 99%

A Randomized Controlled Trial of Early versus Late Surgical Decompression for Thoracic and Thoracolumbar Spinal Cord Injury in 73 Patients

Haghnegahdar

Behjat

Saadat

et al. 2020

Neurotrauma Reports

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Convincing clinical evidence exists to support early surgical decompression in the setting of cervical spinal cord injury (SCI). However, clinical evidence on the effect of early surgery in patients with thoracic and thoracolumbar (from T1 to L1 [T1-L1]) SCI is lacking and a critical knowledge gap remains. This randomized controlled trial (RCT) sought to evaluate the safety and efficacy of early (<24 h) compared with late (24-72 h) decompressive surgery after T1-L1 SCI. From 2010 to 2018, patients (‡16 years of age) with acute T1-L1 SCI presenting to a single trauma center were randomized to receive either early (<24 h) or late (24-72 h) surgical decompression. The primary outcome was an ordinal change in American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade at 12-month follow-up. Secondary outcomes included complications and change in ASIA motor score (AMS) at 12 months. Outcome assessors were blinded to treatment assignment. Of 73 individuals whose treatment followed the study protocol, 37 received early surgery and 36 underwent late surgery. The mean age was 29.74-11.4 years. In the early group 45.9% of patients and in the late group 33.3% of patients had a ‡1-grade improvement in AIS (odds ratio [OR] 1.70, 95% confidence interval [CI]: 0.66-4.39, p = 0.271); significantly more patients in the early (24.3%) than late (5.6%) surgery group had a ‡2-grade improvement in AIS (OR 5.46, 95% CI: 1.09-27.38, p = 0.025). There was no statistically significant difference in the secondary outcome measures. Surgical decompression within 24 h of acute traumatic T1-L1 SCI is safe and is associated with improved neurological outcome, defined as at least a 2-grade improvement in AIS at 12 months.

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Global burden of traumatic brain and spinal cord injury

Cited by 189 publications

References 8 publications

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

The effects of mouse strain and age on a model of unilateral cervical contusion spinal cord injury

A Randomized Controlled Trial of Early versus Late Surgical Decompression for Thoracic and Thoracolumbar Spinal Cord Injury in 73 Patients

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