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Chondroitinase ABC promotes functional recovery after spinal cord injury

Nature volume 416, pages 636–640 (2002)Cite this article

Abstract

The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs)1,2. CSPGs are inhibitory to axon growth in vitro3,4,5, and regenerating axons stop at CSPG-rich regions in vivo6. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity7,8,9,10. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries.

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Figure 1: ChABC degrades CS-GAG in vivo.
Figure 2: ChABC induces upregulation of GAP-43 in lesioned DRG neurons and regeneration of dorsal column axons.
Figure 3: ChABC promotes regeneration of corticospinal tract axons.
Figure 4: ChABC restores functional connections of descending motor pathways.
Figure 5: Functional recovery after ChABC treatment.

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Acknowledgements

We thank T. J. Boucher for critical review of the manuscript and J. V. Priestley, M. Lidierth, B. J. Kerr and M. S. Ramer for their help. This work was supported by The Wellcome Trust, MRC, International Spinal Research Trust and Action Research.

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Author notes

  1. Lawrence D. F. Moon

    Present address: Miami Project to Cure Paralysis, 1095 NW 14th Terrace, Mail Locator R-48, PO Box 16960, Miami, Florida, 33101, USA

Authors and Affiliations

  1. Sensory Function Group, Centre for Neuroscience Research, Hodgkin Building, Kings College London, Guy's Campus, London Bridge, London, SE1 1UL, UK

    Elizabeth J. Bradbury, Reena J. Popat, Gavin S. Bennett, Preena N. Patel & Stephen B. McMahon

  2. Department of Physiology and Centre for Brain Repair, University of Cambridge, Robinson Way, Cambridge, CB2 2PY, UK

    Lawrence D. F. Moon & James W. Fawcett

  3. Department of Neuroscience, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK

    Von R. King

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Correspondence to Elizabeth J. Bradbury.

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Bradbury, E., Moon, L., Popat, R. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002). https://doi.org/10.1038/416636a

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