Regeneration of Brainstem-Spinal Axons after Lesion and Immunological Disruption of Myelin in Adult Rat

Dyer, Jason K.; Bourque, Jason; Steeves, John D.

doi:10.1006/exnr.1998.6905

Cited by 64 publications

(35 citation statements)

References 53 publications

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“…Myelin disruption with the GalC antibody permits regeneration of brainstem-spinal axons when administered after acute hemisection in the adult rat. 68 More recently, we have found that immunological myelin disruption stimulates both regeneration of supraspinal axons and improved recovery of locomotion after severe thoracic contusion injuries (where controls are permanently paralyzed), even when treatment is delayed for 1 or 2 months after injury (JDS, unpublished observations).…”

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 96%

“…We have used a complement-fixing antibody to galactocerebroside (GalC), coadministered intraspinally with serum complement, to achieve transient focal demyelination at the site of SCI. [67][68][69] Within the CNS, GalC is restricted to the cell membrane of oligodendrocytes and myelin; specifically, it is present in the outer layer of the myelin membrane. Binding of the GalC antibody triggers activation of the complement cascade, which results in disruption of myelin membranes and recruitment of endogenous microglia or invading macrophages to phagocytically clear CNS myelin within the injured region.…”

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 99%

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Setting the stage for functional repair of spinal cord injuries: a cast of thousands

2005

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Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast of villains but also a company of therapeutic targets, many of which have yet to be fully exploited. We next discuss recent progress in the fields of bridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects of SCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role.Spinal Cord (2005) 43, 134-161.

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Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 96%

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 99%

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

2005

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“…Recent studies have shown that either the selective disruption of myelin or the targeted functional inhibition of the aforementioned myelin proteins within either the developing and adult avian or mammalian spinal cord can facilitate functional axonal sprouting and/or regeneration. [10][11][12][13][14][15][16] To reduce transiently the axonal growth inhibition activity associated with CNS myelin, we have developed an immunological intraspinal infusion protocol. 17 The immunological process is activated by infusing a myelinspecific IgG antibody to an outer cell surface myelinspecific epitope (eg anti-galactocerebroside or GalC) that has a high affinity for activating the accompanying infusion of serum complement.…”

Section: Introductionmentioning

confidence: 99%

“…Only when combined will these two reagents selectively target CNS myelin to focally demyelinate an injured spinal cord region in a concentration-dependent, diffusion-limited manner. 11,12,14,17,18 When applied to the embryonic chick spinal cord, prior to transection of the cord, 12,17 this treatment suppressed CNS myelin development and extended the normal permissive period for axonal regeneration and functional recovery to later stages of development. 12,17 In the mature spinal cord of posthatchling birds, the same immunological protocol transiently demyelinates *Correspondence: JK Dyer, International Collaboration on Repair Discoveries (ICORD), University of British Columbia, 6270 University Boulevard, Vancouver, BC, Canada V6T 1Z4 and disrupts compact myelin, thereby facilitating some functional axonal regeneration of axotomized avian brainstem-spinal neurons, albeit at a reduced level of repair when compared to the injured developing spinal cord.…”

Section: Introductionmentioning

confidence: 99%

“…14 The compacted form of myelin subsequently reappears after the immunological protocol is discontinued. 14,19 More recent work in the adult rat spinal cord indicates that a similar immunological treatment after a thoracic cord lesion also facilitates anatomical regrowth of axonal projections from specific brainstem-spinal nuclei, 11 as well as ascending dorsal column neurons. 18 These studies indicated that this immunological protocol is effective in transiently removing the inhibitory effects of CNS myelin against axonal repair in both the developing and adult spinal cord of different species and will facilitate functional axonal regeneration.…”

Section: Introductionmentioning

confidence: 99%

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The role of complement in immunological demyelination of the mammalian spinal cord

2005

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Study design: Specificity of serum complement component to elicit immunological demyelination. Objectives: To assess the role of complement components and pathways in experimental immunological demyelination of the adult rat spinal cord. Setting: ICORD, University of British Columbia, Vancouver, Canada. Subjects: We used 32 adult male Sprague-Dawley rats, of approximately 220 g weight. Methods: Rats received intraspinal infusions of demyelinating reagents, delivered by osmotic minipump, for a 7-day infusion at 0.5 ml/h. Reagents consisted of a polyclonal antibody to galactocerebroside and human serum complement. Complement sera deficient for a single component were used to assess the role of the alternative pathway, the classical pathway, and the membrane attack complex. Demyelination was assessed, at 7 days, ultrastructurally. Results: Removal of C3 protein, common to classical and alternative complement pathways, or C4 protein, a classical pathway protein, resulted in no demyelination. However, complement deficient in Factor B, an alternative pathway protein, produced effective demyelination. Upon removal of C5 or C6, membrane attack complex proteins, demyelination was also observed. Conclusion: This suggests that the classical pathway is sufficient for the protocol to demyelinate the adult rat spinal cord, and that the membrane attack complex is also not required.Spinal Cord (2005) 43, 417-425.

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Tenascin-R inhibits regrowth of optic fibers in vitro and persists in the optic nerve of mice after injury

Becker

Anliker

Becker

et al. 2000

Glia

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Tenascin‐R, an extracellular matrix constituent expressed by oligodendrocytes and some neuronal cell types, may contribute to the inhibition of axonal regeneration in the adult central nervous system. Here we show that outgrowth of embryonic and adult retinal ganglion cell axons from mouse retinal explants is significantly reduced on homogeneous substrates of tenascin‐R or a bacterially expressed tenascin‐R fragment comprising the epidermal growth factor‐like repeats (EGF‐L). When both molecules are presented as a sharp substrate border, regrowing adult axons do not cross into the tenascin‐R or EGF‐L containing territory. All in vitro experiments were done in the presence of laminin, which strongly promotes growth of embryonic and adult retinal axons, suggesting that tenascin‐R and EGF‐L actively inhibit axonal growth. Contrary to the disappearance of tenascin‐R from the regenerating optic nerve of salamanders (Becker et al., J Neurosci 19:813–827, 1999), the molecule remains present in the lesioned optic nerve of adult mice at levels similar to those in unlesioned control nerves for at least 63 days post‐lesion (the latest time point investigated), as shown by immunoblot analysis and immunohistochemistry. In situ hybridization analysis revealed an increase in the number of cells expressing tenascin‐R mRNA in the lesioned nerve. We conclude that, regardless of the developmental stage, growth of retinal ganglion cell axons is inhibited by tenascin‐R and we suggest that the continued expression of the protein after an optic nerve crush may contribute to the failure of adult retinal ganglion cells to regenerate their axons in vivo. GLIA 29:330–346, 2000. © 2000 Wiley‐Liss, Inc.

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Regeneration of Brainstem-Spinal Axons after Lesion and Immunological Disruption of Myelin in Adult Rat

Cited by 64 publications

References 53 publications

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

The role of complement in immunological demyelination of the mammalian spinal cord

Tenascin-R inhibits regrowth of optic fibers in vitro and persists in the optic nerve of mice after injury

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