Chondroitinase ABC has a long-lasting effect on chondroitin sulphate glycosaminoglycan content in the injured rat brain.
Chondroitin sulphate proteoglycans (CSPGs) are axon growth inhibitory molecules present in the glial scar that play a part in regeneration failure after damage to the CNS and which restrict CNS plasticity. Removal of chondroitin sulphate glycosaminoglycan (GAG) chains with chondroitinase-ABC (chABC) in models of CNS injury promotes both axon regeneration and plasticity. We have analysed the immediate and long-term effects of a single injection of chABC on CSPGs, GAGs and axon regeneration. We made unilateral nigrostriatal lesions in adult rats accompanied by an adjacent infusion of either chABC or a bacterial-derived control enzyme (penicillinase). Within 24 h of chABC treatment there was digestion of GAGs, including hyaluronan, and a reduction in neurocan in an area extending 1.5 mm around the injection site. Around 50% of GAG is inaccessible to chABC digestion, even in tissue digested in vitro, which probably represents intracellular stores. In control penicillinase treated animals, total GAGs recovered from the lesioned brains were up-regulated by 4-fold 7 days after injury and gradually decreased to normal at 28 days post-lesion. In chondroitinase-treated animals, the total GAG remained at low level throughout the 28-day experimental period. This suggests the persistence of active chABC for at least 10 days after injection which is able to digest CSPGs released from cells during this time. This was confirmed by immunological detection of enzyme for 10 days and by retrieval of active enzyme from the brain at 10 days after injection. Our results suggest that a single injection of chABC can produce an environment conducive to CNS repair for over 10 days.
Lin
Rachel
R
Cambridge University Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Kwok
Jessica C F
JC
Crespo
Damaso
D
Fawcett
James W
JW
D000818:Animals; D001369:Axons / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology*; D002810:Chondroitinases and Chondroitin Lyases / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D008474:Medial Forebrain Bundle / Q000293:injuries; D009416:Nerve Regeneration / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D006025:Glycosaminoglycans; C013786:A73025; D014446:Tyrosine 3-Monooxygenase; D002810:Chondroitinases and Chondroitin Lyases