Retrograde Axonal Degeneration (“Dieback”) in the Corticospinal Tract after Transection Injury of the Rat Spinal Cord: A Confocal Microscopy Study

Seif, Gamal I.; Nomura, Hiroshi; Tator, Charles H.

doi:10.1089/neu.2007.0323

Cited by 46 publications

(31 citation statements)

References 36 publications

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“…Interestingly, although some conflicting results have been obtained, 50 different studies have consistently supported the inability of regenerating CST axons to enter into the injury site in different models of spinal cord injury such as contusion 10,51 and dorsal hemisection. [52][53][54][55][56] Altogether, these observations raise the possibility that axonal Ryk expression might not be restricted to CST axons and, therefore, that axons belonging to different tracts might be able to express this receptor after SCI. Nevertheless, it should be noted that in the injury model used to perform the present study, few CST axons were observed caudally to the lesion site, clearly indicating that several CST axons were spared after the induction of the damage.…”

Section: Discussionmentioning

confidence: 96%

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

González

Fernández-Martos

Arenas

et al. 2013

Journal of Neurotrauma

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Wnt proteins play a critical role in central nervous system development and have been implicated in several neuropathologies, including spinal cord injury (SCI). Ryk, an unconventional Wnt receptor, regulates axonal regeneration after SCI, although its expression pattern in this neuropathology remains unclear. Therefore, we sought to define the spatiotemporal and cellular pattern of Ryk expression after a contusive SCI in adult rats using quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis. Under physiological conditions, Ryk is expressed in neurons, astrocytes, and blood vessels, but not in oligodendrocytes, microglia, NG2+ glial precursor cells, or axonal projections. Following SCI, we observed an increase in Ryk mRNA expression from 24 h post-injury until 7 days post-injury, whereas its protein levels were significantly augmented at 7 and 14 days post-injury. Moreover, the spatial and cellular Ryk expression pattern was altered in the damaged tissue, where this receptor was observed in reactive astrocytes and microglia/macrophages, NG2+ glial precursors, fibronectin + cells, oligodendrocytes, and axons. In conclusion, we demonstrate that Ryk is expressed in the unlesioned spinal cord and that, after SCI, its spatiotemporal and cellular expression pattern changed dramatically, being expressed in cells involved in the spinal cord response to damage.

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Section: Discussionmentioning

confidence: 96%

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

González

Fernández-Martos

Arenas

et al. 2013

Journal of Neurotrauma

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“…Interestingly, despite marked increase in local sprouting of the CST at points rostral to the lesion; we found no evidence of long-distance regeneration of the CST fibers toward and below the lesion site. This may be related to different factors, including the significant length of axonal die-back in the CST in the chronically injured spinal cord (Seif et al, 2007), the extended central cavity within the chronic lesion that dramatically disrupts the integrity of the CST (Thuret et al, 2006), the presence of myelin debris (Schwab and Bartholdi, 1996;Schwab, 2002Schwab, , 2004 and/or macrophages (Horn et al, 2008;Busch et al, 2009) that pose a barrier to regenerating axons around the lesion, and the residual CSPGs that have been unaffected by our ChABC treatment.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Transplanted Adult Neural Stem/Progenitor Cells, Chondroitinase, and Growth Factors Promote Functional Repair and Plasticity of the Chronically Injured Spinal Cord

Karimi-Abdolrezaee¹,

Eftekharpour²,

Wang³

et al. 2010

J. Neurosci.

333

378

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The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

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“…As axons of axotomized upper motoneurons progressively retract from the lesion site (Pallini et al, 1988;Seif et al, 2007) and often atrophy (Wannier et al, 2005), they may become less responsive to anti-Nogo-A treatment with increasing time after injury. In addition, scar formation and accumulation of CSPGs at the injury site may further impede successful regeneration (Busch and Silver, 2007), which could further reduce the efficacy of neurite growth-enhancing treatments.…”

Section: Introductionmentioning

confidence: 99%

Delayed Anti-Nogo-A Antibody Application after Spinal Cord Injury Shows Progressive Loss of Responsiveness

Gonzenbach¹,

Zoerner

Schnell

et al. 2012

Journal of Neurotrauma

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Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogoreceptor antagonists, or inhibition of the downstream mediator RhoA/ROCK in adult rodents. Proofof-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1-or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1-week-delayed treatments, but not when the antibody treatment was started with a delay of 2 weeks. Swimming and narrow beam crossing recovered well in rats treated acutely or with a 1-week delay with anti-Nogo-A antibodies, but not in the 2-week-delayed group. These results show that the time frame for treatment of spinal cord lesions with anti-Nogo-A antibodies is restricted to less than 2 weeks in adult rodents. Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogo-receptor antagonists, or inhibition of the downstream mediator RhoA/ ROCK in adult rodents. Proof-of-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1-or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1-week-delayed treatments, but not when the antibody treatment was started with a delay of 2 weeks. Swimming and narrow beam crossin...

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Retrograde Axonal Degeneration (“Dieback”) in the Corticospinal Tract after Transection Injury of the Rat Spinal Cord: A Confocal Microscopy Study

Cited by 46 publications

References 36 publications

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

Synergistic Effects of Transplanted Adult Neural Stem/Progenitor Cells, Chondroitinase, and Growth Factors Promote Functional Repair and Plasticity of the Chronically Injured Spinal Cord

Delayed Anti-Nogo-A Antibody Application after Spinal Cord Injury Shows Progressive Loss of Responsiveness

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