Chondroitinase ABC promotes functional recovery after spinal cord injury.
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). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. 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.
Bradbury
Elizabeth J
EJ
Sensory Function Group, Centre for Neuroscience Research, Hodgkin Building, Kings College London, Guy's Campus, London Bridge, London SE1 1UL, UK. elizabeth.bradbury@kcl.ac.uk
Moon
Lawrence D F
LD
Popat
Reena J
RJ
King
Von R
VR
Bennett
Gavin S
GS
Patel
Preena N
PN
Fawcett
James W
JW
McMahon
Stephen B
SB
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D019765:Chondroitin ABC Lyase / Q000378:metabolism* / Q000627:therapeutic use*; D004594:Electrophysiology; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009043:Motor Activity; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D011597:Psychomotor Performance; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D015854:Up-Regulation
D019922:GAP-43 Protein; D007527:Isoenzymes; C087857:protein kinase C gamma; D011493:Protein Kinase C; D019765:Chondroitin ABC Lyase