Putative Inhibitory Extracellular Matrix Molecules at the Dorsal Root Entry Zone of the Spinal Cord during Development and after Root and Sciatic Nerve Lesions

Pindzola, Ronda R.; Doller, Catherine; Silver, Jerry

doi:10.1006/dbio.1993.1057

Cited by 238 publications

(167 citation statements)

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“…The NG2 proteoglycan is increased after CNS injury by oligodendrocyte precursor cells (Levine, 1994;Rhodes et al, 2006), phosphacan is upregulated within glial scars (McKeon, et al, 1995), and phosphacan, brevican, versican, and neurocan are all produced within the injured spinal cord (Jones, et al, 2003a). Chondroitin sulfate proteoglycans are found in the brain after stab wound (Fitch and Silver, 1997a), in the spinal cord after injury to the dorsal root (Pindzola et al, 1993), and in the spinal cord following injury (Fitch and Silver, 1997a;Jones, et al, 2003a;Jones et al, 2003b). The rapid and long lasting upregulation of proteoglycans within the vicinity of the glial scar has implicated them in the creation of nonpermissive growth environments in the CNS, similar to their role in boundary formation within the CNS during development (Fitch and Silver, 1997b;Grimpe and Silver, 2004;Silver, 1994;Snow et al, 1990).…”

Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

869

657

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Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

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Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

869

657

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“…Although CSPGs play a restrictive role and are essential for axonal guidance during normal development (Pindzola et al, 1993;, these inhibitory molecules form a chemical barrier that arrests regenerative axons in adults despite the absence of glial scarring (Davies et al, 1997). Enzymatic treatment of the injured spinal cord with chondroitinase ABC, which attenuates CSPG activity, markedly improves axonal regeneration and functional recovery (Bradbury et al, 2002;Chau et al, 2004).…”

Section: Inhibitory Cspgs and Mmpsmentioning

confidence: 99%

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Hsu¹,

McKeon²,

Goussev³

et al. 2006

J. Neurosci.

205

184

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.

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“…CSPG disruption in three-dimensional astrocyte cultures or on cryosections of adult spinal cord increases axonal elongation (Smith- Thomas et al, 1995;Zuo et al, 1998b). Spinal CSPG expression begins during the first postnatal week, coinciding perfectly with the end of the permissive period of the DREZ (Pindzola et al, 1993), and dorsal rhizotomy further upregulates CSPG expression (Pindzola et al, 1993;Zhang et al, 1999). Direct lesions to the CNS induce CSPG deposition at the lesion site, which halts the axonal progress of transplanted DRG neurons (Davies et al, 1997(Davies et al, , 1999.…”

Section: Barrier One: Astrocytesmentioning

confidence: 99%

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

Ramer

Duraisingam²,

Priestley

et al. 2001

J. Neurosci.

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Glial-derived inhibitory molecules and a weak cell-body response prevent sensory axon regeneration into the spinal cord after dorsal root injury. Neurotrophic factors, particularly neurotrophin-3 (NT-3), may increase the regenerative capacity of sensory neurons after dorsal rhizotomy, allowing regeneration across the dorsal root entry zone (DREZ). Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 primarily in large-diameter sensory profiles (which did not occur after rhizotomy alone), as well as regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn. However, delaying treatment for 1 week compromised regeneration: although axons still penetrated the DREZ, growth within white matter was qualitatively and quantitatively restricted. This was not associated with an impaired cell-body response (GAP-43 upregulation was equivalent for both immediate and delayed treatments), or with astrogliosis at the DREZ, which begins almost immediately after rhizotomy, but with the delayed appearance of mature ED1-expressing phagocytes in the dorsal white matter between 1 and 2 weeks after lesion, marking the beginning of myelin breakdown. After rhizotomy with immediate NT-3 treatment, regeneration continues beyond 2 weeks, but in the dorsal gray matter rather than in the degenerating dorsal columns. The ability of NT-3 to promote regeneration across the DREZ, but not after the beginning of degeneration after delayed treatment reveals a hierarchy of inhibitory influences: the astrogliotic, but not the degenerative barrier is surmountable by NT-3 treatment. Key words: neurotrophin-3; regeneration; degeneration; astrocytes; oligodendrocytes; myelin; dorsal root ganglionThe differential abilities of peripheral and central nervous tissue to support regeneration is exemplified at the dorsal root entry zone (DREZ), which marks the entry point of primary afferent axons into the spinal cord. Here, the environment changes abruptly from consisting of growth-permissive Schwann cells, to astrocytes, oligodendrocytes, and microglia, which may all inhibit regeneration (Fawcett and Asher, 1999). On contact with the DREZ, regenerating axons form club-like end bulbs or synapselike structures, (Ramon y Cajal, 1928;Carlstedt, 1985), but because of the prohibitive environment of the CNS and a paltry regenerative response of sensory neurons to rhizotomy, they never re-enter the adult cord.One strategy to encourage regeneration is to enhance the growth response of the rhizotomized neurons. GAP-43 is induced in nearly all neurons during peripheral nerve regeneration (Verge et al., 1990b), but in few neurons after rhizotomy (Schreyer and Skene, 1993), unless the root is severed very close to the DRG (Chong et al., 1996). Dorsal root axonal growth occurs at about half the rate of peripheral axons (Wujek and Lasek, 1983;Oblinger and Lasek, 1984). An experimental "conditioning" lesion to a peripheral nerve before dorsal rhizotomy doubles the rate of ...

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Putative Inhibitory Extracellular Matrix Molecules at the Dorsal Root Entry Zone of the Spinal Cord during Development and after Root and Sciatic Nerve Lesions

Cited by 238 publications

References 0 publications

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

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