A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice^†

Abstract

Chondroitin sulphate proteoglycan (CSPG) inhibits axonal regeneration in the central nervous system (CNS) and its local degradation promotes repair. We postulated that the enzymatic degradation of CSPG generates reparative products. Here we show that an enzymatic degradation product of CSPG, a specific disaccharide (CSPG-DS), promoted CNS recovery by modulating both neuronal and microglial behaviour. In neurons, acting via a mechanism that involves the PKCalpha and PYK2 intracellular signalling pathways, CSPG-DS induced neurite outgrowth and protected against neuronal toxicity and axonal collapse in vitro. In microglia, via a mechanism that involves ERK1/2 and PYK2, CSPG-DS evoked a response that allowed these cells to manifest a neuroprotective phenotype ex vivo. In vivo, systemically or locally injected CSPG-DS protected neurons in mice subjected to glutamate or aggregated beta-amyloid intoxication. Our results suggest that treatment with CSPG-DS might provide a way to promote post-traumatic recovery, via multiple cellular targets.

Knocking Down Glycosaminoglycan Synthesis

“…Another possibility, however, is that the products of CSPG GAG degradation may enhance axon repair. This hypothesis has been supported by Rolls et al (2004), who demonstrated that GAG disaccharide units released from cABC-mediated CSPG GAG degradation could stimulate axon repair by promoting axon outgrowth, overcoming the effects of strong repulsive factors, and activating the neuroprotective phenotype of endogenous microglia. Therefore, cABC treatment might stimulate axon regeneration by releasing GAG disaccharides.…”

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

“…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).…”

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

“…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] . The enzyme remains active in vivo for 10 days after injection.…”