Steroids for acute spinal cord injury

Mb, Bracken

doi:10.1002/14651858.cd001046

Cited by 193 publications

(179 citation statements)

References 21 publications

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“…1−7 Notably, high and multiple CS doses are frequently used during periods of developmental myelination, 8,9 and to treat conditions involving myelin injury/repair such as multiple sclerosis and spinal cord injury. 10,11 The cellular mechanisms underpinning the reported CS induced defects in myelin genesis are largely unknown, but observations that myelination delays occur without accompanying axon loss 2,5 indicate that such effects may be primarily underpinned by glial responses to CS.…”

mentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.

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mentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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“…While I will endeavor to address the first question, I will defer on the second: I will not presume to add my opinions to the long list of authorities that have weighed in on one side or the other on the subject. [6][7][8][9] It could be justifiably claimed that the clinical trial era of SCI research began in February of 1979 with the enrollment of the first patient in a multicenter double-blind randomized control trial (RCT) of MP that was the first of three National Acute SCI Study (NASCIS) trials to be performed under the leadership of the NASCIS Group. 10 The NASCIS 1 trial, a test of 'high dose' (1000 mg bolus and daily thereafter for 10 days) vs 'standard dose' (100 mg bolus and daily thereafter for 10 days) MP began in an era when corticosteroid treatment of acute SCI was widespread and without firm clinical evidence basis (although the majority of pre-clinical laboratory studies had been supportive).…”

Section: The Methylprednisolone Story Nascis 1: Prevailing Dogma Is Omentioning

confidence: 99%

“…While a thorough review of the various positions is well beyond the scope of this communication, the interested reader is encouraged to consult the abundant literature on the topic that has been published over the past 20 years. [6][7][8][9]14,15 A few key points should be considered in the context of lessons, which may be taken from this experience. The primary end point of the trials was a change in neurological function on the basis of a very complex measurement scheme with expanded motor (70 point)/sensory (58 point) scores (with data from only the right extremities used in the analysis), 5 motor/5 sensory categorizations, 3 broad categorizations of completeness and 5 completeness-by-level categorizations-yet there was no categorization of discreet segmental level.…”

Section: The Methylprednisolone Story Nascis 1: Prevailing Dogma Is Omentioning

confidence: 99%

Clinical trials in spinal cord injury: lessons learned on the path to translation. The 2011 International Spinal Cord Society Sir Ludwig Guttmann Lecture

Lammertse

2012

Spinal Cord

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After three decades of clinical research on interventions to improve neurological outcomes in persons with spinal cord injury (SCI), the promise of preclinical discovery has yet to be translated into a consensus standard of care treatment. Nonetheless, SCI researchers remain hopeful that advances in preclinical discovery coupled with improved clinical trial performance will yield effective restorative treatment. This historical review of key studies in SCI over the past 30 years illustrates the progress that has been achieved in establishing a high standard in the conduct of clinical research while providing important lessons for improving trial design, conduct and reporting. Through application of these lessons, the performance of SCI trials can be improved, thereby shortening the pathway to successful translation and the development of effective therapies.

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“…He further reported that high-dose MP therapy was also effective for whiplash injuries and for improving recovery after surgery for lumbar disc disease. 16 Following publication of the NASCIS studies, clinicians began to take a closer look at the data. Nesathurai critically reviewed the NASCIS 2 and NASCIS 3 trials and found that the positive results claimed by researchers in NASCIS 2 and NASCIS 3 had not been reproduced.…”

Section: Reviewmentioning

confidence: 99%

“…They questioned some methodologic issues in the core trials that had been analyzed in the Cochrane Library review. 16 In these studies, neurologic improvement was measured by calculating the difference between two neurologic exam scores taken on admission and at each follow-up time interval. Motor function over 14 motor segments was evaluated by two examiners using a six-point scale between 0 and 5, yielding a total score between 0 and 70.…”

Section: Reviewmentioning

confidence: 99%