Review How does chondroitinase promote functional recovery in the damaged CNS? Dámaso Crespo 1,2 , Richard A. Asher ⁎ ,1 , Rachel Lin, Kate E. Rhodes, James W. Fawcett Cambridge University Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK Received 27 April 2007; revised 28 April 2007; accepted 2 May 2007 Available online 8 May 2007 Abstract A number of recent studies have established that the bacterial enzyme chondroitinase ABC promotes functional recovery in the injured CNS. The issue of how it works is rarely addressed, however. The effects of the enzyme are presumed to be due to the degradation of inhibitory chondroitin sulphate GAG chains. Here we review what is known about the composition, structure and distribution of the extracellular matrix in the CNS, and how it changes in response to injury. We summarize the data pertaining to the ability of chondroitinase to promote functional recovery, both in the context of axon regeneration and the reactivation of plasticity. We also present preliminary data on the persistence of the effects of the enzyme in vivo, and its hyaluronan-degrading activity in CNS homogenates in vitro. We then consider precisely how the enzyme might influence functional recovery in the CNS. The ability of chondroitinase to degrade hyaluronan is likely to result in greater matrix disruption than the degradation of chondroitin sulphate alone. © 2007 Elsevier Inc. All rights reserved. Keywords: Chondroitin sulphate; Extracellular matrix; Hyaluronan; Plasticity; Proteoglycan; Regeneration Contents Introduction ................................................................ 160 Chondroitin sulphate proteoglycans: structure, isoforms and distribution ................................. 160 Structure ............................................................... 160 Isoforms ............................................................... 161 Distribution .............................................................. 161 Specificity of different chondroitinases .................................................. 162 Role of CSPGs in the injured CNS: the glial scar and axon regeneration ................................ 162 Role of CSPGs in the injured CNS: reactivation of plasticity ...................................... 163 Effects of chondroitinase on CSPGs in vivo ............................................... 163 Effects of chondroitinase on CSPGs in vitro ............................................... 165 Chondroitinase delivery .......................................................... 165 How might chondroitinase affect CNS function? ............................................. 166 Receptor-mediated effects....................................................... 166 Blocking axon growth-promoting sites in the ECM ......................................... 166 Release of bound factors ....................................................... 166 Immune responses .......................................................... 167 Effects of digestion products ..................................................... 167 Digestion of hyaluronan ....................................................... 167 Experimental Neurology 206 (2007) 159 – 171 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Fax: +44 1223 331174. E-mail address: raa24@cam.ac.uk (R.A. Asher). 1 These authors contributed equally. 2 Permanent address: Dpto. de Anatomia y Biologia Celular, Universidad de Cantabria, Avda. Cardenal Herrera Oria, s/n 39011 Santander, Spain. 0014-4886/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2007.05.001