How does chondroitinase promote functional recovery in the damaged CNS?

Crespo, David Revuelta; Asher, Richard; Lin, Rachel; Rhodes, Kate; Fawcett, James W.

doi:10.1016/j.expneurol.2007.05.001

Cited by 124 publications

(112 citation statements)

References 163 publications

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“…Importantly, intact axons only sprout where CSPG digestion, degeneration, and denervation occur [57,78]. This suggests that chABC may modulate immune/inflammatory responses, liberate extracellular matrix-bound facilitatory factors, and overcome interactions between inhibitory CSPGs and extracellular matrix molecules in the injured CNS (reviewed in Crespo et al [85], Bradbury and Carter [86]). Attenuating the decline in axonal conduction through the SCI site could be involved [87].…”

Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 99%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

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Summary: Motor, sensory, and autonomic functions can spontaneously return or recover to varying extents in both humans and animals, regardless of the traumatic spinal cord injury (SCI) level and whether it was complete or incomplete. In parallel, adverse and painful functions can appear. The underlying mechanisms for all of these diverse functional changes are summarized under the term plasticity. Our review will describe what is known regarding this phenomenon after traumatic SCI and focus on its relevance to motor and sensory recovery. Although it is still somewhat speculative, plasticity can be found throughout the neuraxis and includes various changes ranging from alterations in the properties of spared neuronal circuitries, intact or lesioned axon collateral sprouting, and synaptic rearrangements. Furthermore, we will discuss a selection of potential approaches for facilitating plasticity as possible SCI treatments. Because a mechanism underlying spontaneous plasticity and recovery might be motor activity and the related neuronal activity, activity-based therapies are being used and investigated both clinically and experimentally. Additional pharmacological and gene-delivery approaches, based on plasticity being dependent on the delicate balance between growth inhibition and promotion as well as the basic intrinsic growth ability of the neurons themselves, have been found to be effective alone and in combination with activitybased therapies. The positive results have to be tempered with the reality that not all plasticity is beneficial. Therefore, a tremendous number of questions still need to be addressed. Ultimately, answers to these questions will enhance plasticity's potential for improving the quality of life for persons with SCI.

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Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 99%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

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“…Chondroitin sulfate proteoglycans are also potent inhibitors of neurite outgrowth in vitro [47] and growth of damaged axons in vivo [48,49]. CSPGs together with hyaluronan and tenascins make up the extracellular matrix of the CNS.…”

Section: Astroglial Scars and Cspgsmentioning

confidence: 99%

“…CSPGs consist of a core protein to which a variable number of unbranched sugar (glucosaminoglycan; GAG) side chains are covalently attached. Hydrolyzing GAG side chains with the bacterial enzyme chondroitinase ABC (ChABC) has been shown to make extracellular matrix-rich substrata more permissive to neurite outgrowth [49]; however, stubs (carbohydrate linker regions) remain after hydrolysis which retain some inhibitory activity [50], and furthermore proteogylcan core proteins might also be inhibitory irrespective of their GAG status [51]. Inhibitory CSPGs are robustly expressed in the adult CNS [48] and their expression is greatly elevated at sites of CNS lesion and are the major inhibitory species associated with the glial scar.…”

Section: Astroglial Scars and Cspgsmentioning

confidence: 99%

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cafferty

McGee

Strittmatter

2008

Trends in Neurosciences

142

108

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Loss of function after neurological injury frequently occurs through the interruption of axonal connectivity, rather than through cell loss. Functional deficits persist because a multitude of inhibitory factors in degenerating myelin and astroglial scar prevent axonal growth in the adult brain and spinal cord. Given the high clinical significance of achieving functional recovery through axonal growth, substantial research effort has been, and will be, devoted toward this desirable goal. Unfortunately, the labels commonly used in the literature to categorize post-injury axonal anatomy might hinder advancement. In this article, we present an argument for the importance of developing precise terms that describe axonal growth in terms of the inciting event, the distance of axonal extension and the timing of axonal growth. The phenotypes produced by molecular interventions that overcome astroglial scar or myelin-associated inhibitors are reframed and discussed in this context.

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“…it degrades CSPGs by cleaving the GAG chains into soluble disaccharides or tetrasaccharides, and leaves behind the core protein. This enzymatic digestion results in the release of bound growth factors from chondroitin sulfate GAG chains [9] , and reduction of the glial scar neoepitopeinduced immune response [10] . Also, one of the digestion products, the chondroitin sulfate E-disaccharide, is growthpromoting [11] .…”

Section: Introductionmentioning

confidence: 99%

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

Zhao

Fawcett

2013

Neurosci. Bull.

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After spinal cord injury (SCi), re-establishing functional circuitry in the damaged central nervous system (CNS) faces multiple challenges including lost tissue volume, insufficient intrinsic growth capacity of adult neurons, and the inhibitory environment in the damaged CNS. Several treatment strategies have been developed over the past three decades, but successful restoration of sensory and motor functions will probably require a combination of approaches to address different aspects of the problem. Degradation of the chondroitin sulfate proteoglycans with the chondroitinase ABC (ChABC) enzyme removes a regeneration barrier from the glial scar and increases plasticity in the CNS by removing perineuronal nets. its mechanism of action does not clash or overlap with most of the other treatment strategies, making ChABC an attractive candidate as a combinational partner with other methods. in this article, we review studies in rat SCi models using ChABC combined with other treatments including cell implantation, growth factors, myelin-inhibitory molecule blockers, and ion channel expression. We discuss possible ways to optimize treatment protocols for future combinational studies. To date, combinational therapies with ChABC have shown synergistic effects with several other strategies in enhancing functional recovery after SCi. These combinatorial approaches can now be developed for clinical application.

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How does chondroitinase promote functional recovery in the damaged CNS?

Cited by 124 publications

References 163 publications

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

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