Effects of methylprednisolone and MK-801 on functional recovery after experimental chronic spinal cord injury

Haghighi, Siavash S.; Surdell, Daniel L.; Plambeck, Robert D.; Agrawal, Sandeep; Johnson, Gayle C.; Walker, Angela M.

doi:10.1038/sj.sc.3101074

Cited by 26 publications

(19 citation statements)

References 34 publications

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“…Although MK-801 prevents some SCI-induced cell loss (Liu et al, 1997;Wada et al, 1999), it does not improve blood flow, edema, or locomotor function (Li and Tator, 1999;Haghighi et al, 2000;Li and Tator, 2000). Our results (Tables III-VI and VIII) offer one explanation for the lack of long-term beneficial effects for MK-801 treatment on SCI outcomes.…”

Section: Noninjury-related Effects Of Mk-801 On Spinal Cord Expressiomentioning

confidence: 49%

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

Nešić

Švrakić

et al. 2002

J of Neuroscience Research

102

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Spinal cord injury (SCI)-induced neurodegeneration leads to irreversible and devastating motor and sensory dysfunction. Post-traumatic outcomes are determined by events occurring during the first 24 hours after SCI. An increase in extracellular glutamate concentration to neurotoxic levels is one of the earliest events after SCI. We used Affymetrix DNA oligonucleotide microarrays (with 1,322 DNA probes) analysis to measure gene expression in order to test the hypothesis that SCI-induced N-methyl-D-aspartate (NMDA) receptor activation triggers significant postinjury transcriptional changes. Here we report that SCI, 1 hour after trauma, induced change in mRNA levels of 165 genes and expression sequence tags (ESTs). SCI affected mRNA levels of those genes that regulate predominantly transcription factors, inflammation, cell survival, and membrane excitability. We also report that NMDA receptor inhibition (with -(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate ) reversed the effect of SCI on about 50% of the SCI-affected mRNAs. Especially interesting is the finding that NMDA receptor activation participates in the up-regulation of inflammatory factors. Therefore, SCI-induced NMDA receptor activation is one of the dominant, early signals after trauma that leads to changes in mRNA levels of a number of genes relevant to recovery processes. The majority of MK-801 effects on the SCI-induced mRNA changes reported here are novel. Additionally, we found that the MK-801 treatment also changed the mRNA levels of 168 genes and ESTs that had not been affected by SCI alone, and that some of their gene products could have harmful effects on SCI outcome.

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Section: Noninjury-related Effects Of Mk-801 On Spinal Cord Expressiomentioning

confidence: 49%

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

Nešić

Švrakić

et al. 2002

J of Neuroscience Research

102

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“…17 The development of such therapeutics may be assisted with the delineation SCI mechanisms and their relationship to column injury patterns. It is hoped that clinical therapies may eventually achieve greater success if they are targeted to specific structures damaged by these distinct injury mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A Three-Dimensional Finite Element Model of the Cervical Spine with Spinal Cord: An Investigation of Three Injury Mechanisms

2008

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The spinal cord may be injured through various spinal column injury patterns (e.g., burst fracture, fracture dislocation); however, the relationship between column injury pattern and cord damage is not well understood. A three-dimensional finite element model of a human cervical spine and spinal cord segment was developed, verified using published experimental data, and used to investigate differences in cord strain distributions during various column injury patterns. For a transverse contusion injury, as would occur in a burst fracture, a 33% canal occlusion resulted in two peaks of strain between the indentor and opposing vertebral body and intermediate peak strain values. For a distraction injury, relevant to column distortion injuries, a 2.6 mm axial displacement to the cord resulted in more uniform strains throughout the cord and low peak strain values. For a dislocation injury, as would occur in a fracture dislocation, an anterior displacement of C5 corresponding to 30% of the sagittal dimension of the vertebral body resulted in high peak strain values adjacent to the shearing vertebrae and increased strains in the lateral columns compared to contusion. This model includes more anatomical details compared to previous studies and provides a baseline for mechanical comparisons in spinal cord injury.

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“…First, the dose of rolipram most effective as an antiinflammatory agent is 3-to 6-fold higher than the optimal dose we report here for functional recovery after spinal cord injury (22)(23)(24). Second, methylprednisolone, a known antiinflammatory already used as a therapy in humans, prevents some secondary cell loss in animal models of spinal cord injury but does not produce any significant improvement in functional recovery (25)(26)(27) Regardless, of the mechanism of action, rolipram is effective and should be considered as a therapy for spinal cord injury. It is of note that rolipram is effective at lower but not at high doses, for both the culture and the in vivo assays.…”

Section: Discussionmentioning

confidence: 99%

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

Nikulina

Tidwell

Dai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

310

270

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Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3͞4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.

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Effects of methylprednisolone and MK-801 on functional recovery after experimental chronic spinal cord injury

Cited by 26 publications

References 34 publications

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

A Three-Dimensional Finite Element Model of the Cervical Spine with Spinal Cord: An Investigation of Three Injury Mechanisms

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

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