CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury

Wamil, Artur W.; Wamil, Barbara D.; Hellerqvist, Carl G.

doi:10.1073/pnas.95.22.13188

Cited by 56 publications

(32 citation statements)

References 40 publications

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“…For example, with the 5-point scale Tarlov test, no signs of recovery were detected several weeks after severe SCI. 17 Also, no meaningful movements were reported on a 10-point scale, 18 while a score of 2 was found with the BBB 21-point scale 17 in spinal mice few days to few weeks after spinalization. Similar results were reported with these methods in complete spinal rats.…”

Section: Discussionmentioning

confidence: 99%

Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice

Guertin

2004

Spinal Cord

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Study design: Experimental laboratory investigation of hindlimb movement recovery in chronic paraplegic mice. Objectives: Development of an assessment method to discriminatively quantify motor and locomotor-like movements of paraplegic mice. Setting: Laval University Medical Center, Quebec, Canada. Methods: Signs of 'functional recovery' were examined in open-field condition during 1 month in adult mice with a complete spinal cord transection at the low-thoracic level. Results: None of the mice exhibited hindlimb movements after spinalization. At 7 days, 33% of them displayed weak nonbilaterally alternating movements (NBA). At 14 days, increased NBA were observed and the first bilaterally alternating movements (BA) in 10% of the mice. A progressive increase of movement frequency and amplitude was found after 2-3 weeks. By the end of the month, 86% displayed mixed NBA and BA. However, none of them recovered the ability to stand or bear their own weight with the hindlimbs. Conclusion: This study reports signs of partial hindlimb movement recovery in chronic paraplegic mice and provides evidence of plasticity in sublesional circuits of neurons occurring in the absence of inputs from the brain, locomotor training or pharmacological treatment. This assessment method can be used to characterize hindlimb movements in complete spinal cord transected mice tested in open-field condition.

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Section: Discussionmentioning

confidence: 99%

Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice

Guertin

2004

Spinal Cord

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“…As putative modulators of angiogenesis, the gelatinases may promote plasticity 47 and/or glial scar formation. 42 Each of these processes would likely have opposing actions on recovery of function. Clearly, future studies will need to address the role of MMPs in the more chronically injured spinal cord, including the functional implications of MMP inhibition during wound healing.…”

Section: Discussionmentioning

confidence: 99%

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Goussev¹,

Hsu²,

Lin³

et al. 2003

Journal of Neurosurgery: Spine

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Object. Matrix metalloproteinases (MMPs), particularly MMP-9/gelatinase B, promote early inflammation and barrier disruption after spinal cord injury (SCI). Early blockade of MMPs after injury provides neuroprotection and improves motor outcome. There is recent evidence, however, that MMP-9 and MMP-2/gelatinase A participate in later wound healing in the injured cord. The authors therefore examined the activity of these gelatinases during revascularization and glial scar formation in the contused murine spinal cord. Methods. Gelatinase activity was evaluated using gelatin zymography 24 hours after a mild, moderate, or severe contusion injury. The active form of MMP-2 was not detected, whereas MMP-9 activity was evident in all SCI groups and rose with increasing injury severity. The temporal expression of gelatinases was then examined using gelatin zymography after a moderate SCI. The active form of MMP-9 was most prominent at 1 day, extended through the early period of revascularization, and returned to control by 14 days. The active form of MMP-2 appeared at 7 days postinjury and remained elevated compared with that documented in sham-treated mice for at least 21 days. Increased MMP-2 activity coincided with both revascularization and glial scar formation. Using in situ zymography, gelatinolytic activity was detected in the meninges, vascular elements, glia, and macrophage-like cells in the injured cord. Results of immunolabeling confirmed the presence of gelatinase in vessels during revascularization and in reactive astrocytes associated with glial scar formation. Conclusions. These findings suggest that although MMP-9 and -2 exhibit overlapping expression during revascularization, the former is associated with acute injury responses and the latter with formation of a glial scar.

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“…An example of the focus on the inflammatory reaction is the use of CMIOI in mice, which has been shown to preserve posttrauma conductivity. 27 Free radicals have been postulated to aggravate the lesion so that scavengers of free radicals have been used with some benefit. 28 The opiod antagonist naloxone has also been applied with apparent success.…”

Section: The Autonomic Motor Systemmentioning

confidence: 99%

Neuropathology: the foundation for new treatments in spinal cord injury

2004

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The first step essential in the search for a cure of human spinal cord injury (SCI) is to appreciate the complexity of the disorder. In this regard, it is not only the loss of ambulation but the sensory and autonomic changes that are equally important in recovery. In addition, there are the serious social emotional psychological and lifestyle effects of SCI which should also be taken into account. It is also true that no two SCI lesions are alike as each is the result of a SCI unique to that individual. Clinically of utmost importance is the segmental level of injury and whether it is complete, incomplete or discomplete (loss of all neurological functions below the injury but with physiological or anatomical continuity of Central nervous system tracts across the lesion). We are not concerned here with primary and secondary prevention or methods designed to limit the severity of the lesion after the event, important as they are, but with the requirements for a cure. Clearly, the greater the number of nerve fibers that can be preserved in the acute stage, the better will be the end result. Our focus at present is on the end-stage lesion with the aim of showing that a cure for SCI will depend upon establishing functionally useful central axonal regeneration and reestablishing physiological reconnections. Existing experimental methods are based on stimulating axonal regeneration by neutralizing inhibitory factors, adding positive trophisms and creating a permissive environment. Better results are obtained by bridging the gap with grafts of peripheral nerves or transplants of Schwann cells and genetically engineered fibroblasts. Recently, the potential for stem cells to enhance this process has created great interest. This is because of the ability of pluripotential cells to differentiate into neural tissue. A cure based on the physiopathology of SCI requires pyramidal, extrapyramidal, sensory, cerebellar and autonomic pathways to be regenerated with their appropriate neurotransmitters restored and reflexes integrated physiologically and in synchrony. In human SCI, there is a very long distance anatomically for axonal regrowth to occur in order to reach their relevant nuclei. This is because of continuing Wallerian degeneration. It also presumes that the target neurons are intact and that there has been no transneuronal degeneration above or below the lesion. Alternatively, in place of regenerated long axons, a multisynaptic pathway may be constructed from stem cells that have developed into neurons. Whether such a pathway would restore useful neurological functions is unknown. At present, the transplant and grafting research teams are exploring these possibilities in experimental animals. Moderate success in gaining axonal regeneration has been reported; however, it must be appreciated that the human lesion differs considerably from that of the experimental animal. In order to be successful, the neuropathology and neurophysiology of human SCI must be taken into account. The purpose of this review is to place the req...

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CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury

Cited by 56 publications

References 40 publications

Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice

Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Neuropathology: the foundation for new treatments in spinal cord injury

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