A reliable method to reduce collagen scar formation in the lesioned rat spinal cord

Following traumatic injury, the formation of a glial scar and deposition of extracellular matrix (ECM) contributes to the regeneration failure in the adult mammalian central nervous system (CNS). Using a postcommissural forni x transection as a brain lesion model in rat, we have previously shown that the collagenous basement membrane (BM) at the lesion site is a major imped iment for axon regeneration. Deposition of BM in this lesion model can be d elayed by administration of the iron chelator 2,2'-bipyridine (BPY), an inh ibitor of prolyl 4-hydroxylase (PH), a key enzyme of collagen biosynthesis. To examine whether this potential therapeutic approach is transferable to other CNS regions, we have chosen the mechanically lesioned rat spinal cord to investigate the effects of BPY administration on BM formation. Due to t he close proximity of the lesion zone to meningeal fibroblasts, a cell-type secreting large amounts of collagen IV, BM deposition was much more extens ive in the spinal cord than in the brain lesion. Neither immediate injectio ns nor continuous application of BPY resulted in a detectable reduction of BM formation in the spinal cord. Only a combination of anti-scarring treatm ents including (i) injection of the more potent PH inhibitor [2,2'-bipyridi ne]-5,5'-dicarboxylic acid (BPY-DCA), (ii) selective inhibition of fibrobla st proliferation and ECM production by S-Br-cAMP, and (iii) continuous appl ication of BPY-DCA, reduced the lesion-induced BM significantly. The presen t results clearly demonstrate, that the exclusive application of BPY accord ing to a protocol designed for treatment of brain lesions is not sufficient to reduce BM formation in the lesioned adult rat spinal cord. (C) 2001 Els evier Science B.V. All rights reserved.