6-sulphated chondroitins have a positive influence on axonal regeneration对轴突再生6-sulphated软骨素有积极的影响.pdfVIP

6-Sulphated Chondroitins Have a Positive Influence on Axonal Regeneration 1 2¤a 2¤b 1 1 Rachel Lin , Thomas W. Rosahl , Paul J. Whiting , James W. Fawcett , Jessica C. F. Kwok * 1 Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom, 2 The Neuroscience Research Centre, Merck, Sharpe and Dohme, Harlow, United Kingdom Abstract Chondroitin sulphate proteoglycans (CSPGs) upregulated in the glial scar inhibit axon regeneration via their sulphated glycosaminoglycans (GAGs). Chondroitin 6-sulphotransferase-1 (C6ST-1) is upregulated after injury leading to an increase in 6-sulphated GAG. In this study, we ask if this increase in 6-sulphated GAG is responsible for the increased inhibition within the glial scar, or whether it represents a partial reversion to the permissive embryonic state dominated by 6-sulphated glycosaminoglycans (GAGs). Using C6ST-1 knockout mice (KO), we studied post-injury changes in chondroitin sulphotransferase (CSST) expression and the effect of chondroitin 6-sulphates on both central and peripheral axon regeneration. After CNS injury, wild-type animals (WT) showed an increase in mRNA for C6ST-1, C6ST-2 and C4ST-1, but KO did not upregulate any CSSTs. After PNS injury, while WT upregulated C6ST-1, KO showed an upregulation of C6ST-2. We examined regeneration of nigrostriatal axons, which demonstrate mild spontaneous axon regeneration in the WT. KO showed many fewer regenerating axons and more axonal retraction than WT. However, in the PNS, repair of the median and ulnar nerves led to similar and normal lev