A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation‐associated neurodegeneration

Rolls, Asya; Cahalon, Liora; Bakalash, Sharon; Avidan, Hila; Lider, Ofer; Schwartz, Michal

doi:10.1096/fj.05-4540fje

Cited by 88 publications

(65 citation statements)

References 88 publications

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“…Effective knockout of PTPσ using lentiviral delivery of small interfering RNAs also led to motor and sensory recovery along with neurite outgrowth (68). However, it has also been shown that the products of CSPG enzymatic digestion encourage neurite outgrowth and have an immunomodulatory role in inflammatory central nervous system lesions (69,70). Therefore, targeting a specific CSPG receptor such as PTPσ, may not produce all the beneficial effects of ChABC.…”

Section: Discussionmentioning

confidence: 99%

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Carwardine

Wong

Fawcett

et al. 2016

Journal of the Neurological Sciences

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A multitude of factors must be overcome following spinal cord injury (SCI) in order to achieve clinical improvement in patients. It is thought that by combining promising therapies these diverse factors could be combatted with the aim of producing an overall improvement in function. Chondroitin sulphate proteoglycans (CSPGs) present in the glial scar that forms following SCI present a significant block to axon regeneration. Digestion of CSPGs by chondroitinase ABC (ChABC) leads to axon regeneration, neuronal plasticity and functional improvement in preclinical models of SCI. However, the enzyme activity decays at body temperature within 24-72 hours, limiting the translational potential of ChABC as a therapy. Olfactory ensheathing cells (OECs) have shown huge promise as a cell transplant therapy in SCI. Their beneficial effects have been demonstrated in multiple small animal SCI models as well as in naturally occurring SCI in canine patients. In the present study, we have genetically modified canine OECs from the mucosa to constitutively produce enzymatically active ChABC. We have developed a lentiviral vector that can deliver a mammalian modified version of the ChABC gene to mammalian cells, including OECs. Enzyme production was quantified using the Morgan-Elson assay that detects the breakdown products of CSPG digestion in cell supernatants. We confirmed our findings by immunolabelling cell supernatant samples using Western blotting. OECs normal cell function was unaffected by genetic modification as demonstrated by normal microscopic morphology and the presence of the low affinity neurotrophin receptor (p75 NGF ) following viral transduction. We have developed the means to allow production of active ChABC in combination with a promising cell transplant therapy for SCI repair.

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Section: Discussionmentioning

confidence: 99%

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Carwardine

Wong

Fawcett

et al. 2016

Journal of the Neurological Sciences

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“…Interestingly, functional recovery was not observed until at least 6 weeks post-SCI, probably because axons retracted from the lesion site after injury, and outgrowth was not initiated until CSPG digestion rendered the substrate permissive to axon growth. Moreover, the effects of chABC may partially be due to antiinflammatory and neuroprotective effects of the soluble disaccharidic end products of chABC-mediated digestion of CSPG (39,40).…”

Section: Discussionmentioning

confidence: 99%

Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury

Lee

McKeon

Bellamkonda

2009

Proc. Natl. Acad. Sci. U.S.A.

288

243

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Chondroitin sulfate proteoglycans (CSPGs) are a major class of axon growth inhibitors that are up-regulated after spinal cord injury (SCI) and contribute to regenerative failure. Chondroitinase ABC (chABC) digests glycosaminoglycan chains on CSPGs and can thereby overcome CSPG-mediated inhibition. But chABC loses its enzymatic activity rapidly at 37°C, necessitating the use of repeated injections or local infusions for a period of days to weeks. These infusion systems are invasive, infection-prone, and clinically problematic. To overcome this limitation, we have thermostabilized chABC and developed a system for its sustained local delivery in vivo, obviating the need for chronically implanted catheters and pumps. Thermostabilized chABC remained active at 37°C in vitro for up to 4 weeks. CSPG levels remained low in vivo up to 6 weeks post-SCI when thermostabilized chABC was delivered by a hydrogel-microtube scaffold system. Axonal growth and functional recovery following the sustained local release of thermostabilized chABC versus a single treatment of unstabilized chABC demonstrated significant differences in CSPG digestion. Animals treated with thermostabilized chABC in combination with sustained neurotrophin-3 delivery showed significant improvement in locomotor function and enhanced growth of cholera toxin B subunitpositive sensory axons and sprouting of serotonergic fibers. Therefore, improving chABC thermostability facilitates minimally invasive, sustained, local delivery of chABC that is potentially effective in overcoming CSPG-mediated regenerative failure. Combination therapy with thermostabilized chABC with neurotrophic factors enhances axonal regrowth, sprouting, and functional recovery after SCI.chondroitin sulfate | glial scar | glycosaminoglycans | hydrogel

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“…One mechanism by which microglial cell activation is reduced after cABC infusion is by the cABC cleavage of CSPGs to a disaccharidic degradation product that has previously been shown to markedly reduce T-cell infiltration and microglial activation after experimental autoimmune encephalomyelitis. 57 Clearly, cABC has a multitude of effects in the brain, in addition to the well-studied sprouting response, that have only just begun to be unraveled.…”

Section: And (E) Gap43mentioning

confidence: 99%

Chondroitinase Enhances Cortical Map Plasticity and Increases Functionally Active Sprouting Axons after Brain Injury

Harris

Nogueira

Verley

et al. 2013

Journal of Neurotrauma

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The beneficial effect of interventions with chondroitinase ABC enzyme to reduce axon growth-inhibitory chondroitin sulphate side chains after central nervous system injuries has been mainly attributed to enhanced axonal sprouting. After traumatic brain injury (TBI), it is unknown whether newly sprouting axons that occur as a result of interventional strategies are able to functionally contribute to existing circuitry, and it is uncertain whether maladaptive sprouting occurs to increase the well-known risk for seizure activity after TBI. Here, we show that after a controlled cortical impact injury in rats, chondroitinase infusion into injured cortex at 30 min and 3 days reduced c-Fos + cell staining resulting from the injury alone at 1 week postinjury, indicating that at baseline, abnormal spontaneous activity is likely to be reduced, not increased, with this type of intervention. c-Fos + cell staining elicited by neural activity from stimulation of the affected forelimb 1 week after injury was significantly enhanced by chondroitinase, indicating a widespread effect on cortical map plasticity. Underlying this map plasticity was a larger contribution of neuronal, rather than glial cells and an absence of c-Fos + cells surrounded by perineuronal nets that were normally present in stimulated naïve rats. After injury, chondroitin sulfate proteoglycan digestion produced the expected increase in growth-associated protein 43-positive axons and perikarya, of which a significantly greater number were double labeled for c-Fos after intervention with chondroitinase, compared to vehicle. These data indicate that chondroitinase produces significant gains in cortical map plasticity after TBI, and that either axonal sprouting and/or changes in perineuronal nets may underlie this effect. Chondroitinase dampens, rather than increases nonspecific c-Fos activity after brain injury, and induction of axonal sprouting is not maladaptive because greater numbers are functionally active and provide a significant contribution to forelimb circuitry after brain injury.

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A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation‐associated neurodegeneration

Cited by 88 publications

References 88 publications

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury

Chondroitinase Enhances Cortical Map Plasticity and Increases Functionally Active Sprouting Axons after Brain Injury

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