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For over 100 years, scientists have tried to understand the mechanisms that lead to the axonal growth seen during development or the lack thereof during regeneration failure after spinal cord injury (SCI). Deoxyribozyme technology as a potential therapeutic to treat SCIs or other insults to the brain, combined with a bioinformatics approach to comprehend the complex protein-protein interactions that occur after such trauma, is the focus of this review. The reader will be provided with information on the selection process of deoxyribozymes and their catalytic sequences, on the mechanism of target digestion, on modifications, on cellular uptake and on therapeutic applications and deoxyribozymes are compared with ribozymes, siRNAs and antisense technology. This gives the reader the necessary knowledge to decide which technology is adequate for the problem at hand and to design a relevant agent. Bioinformatics helps to identify not only key players in the complex processes that occur after SCI but also novel or less-well investigated molecules against which new knockdown agents can be generated. These two tools used synergistically should facilitate the pursuit of a treatment for insults to the central nervous system. [ABSTRACT FROM AUTHOR]

CNS lesions induce production of ECM molecules that inhibit axon regeneration. One major inhibitory family is the chondroitin sulfate proteoglycans (CSPGs). Reduction of their glycosaminoglycan (GAG) chains with chondroitinase ABC leads to increased axon regeneration that does not extend well past the lesion. Chondroitinase ABC, however, is unable to completely digest the GAG chains from the protein core, leaving an inhibitory "stub" carbohydrate behind. We used a newly designed DNA enzyme, which targets the mRNA of a critical enzyme that initiates glycosylation of the protein backbone of PGs, xylosyltransferase-1. DNA enzyme administration to TGF-β-stimulated astrocytes in culture reduced specific GAG chains. The same DNA enzyme applied to the injured spinal cor d reduction of the GAG chains in the lesion penumbra and allowed axons to regenerate around the core of the lesion. Our experiments demonstrate the critical role of PGs, and particularly those in the penumbra, in causing regeneration failure in the adult spinal cord. [ABSTRACT FROM AUTHOR]

We have addressed the question of whether a family of axon growth-promoting molecules known as the laminins may play a role during axon regeneration in the CNS. A narrow sickle-shaped region containing a basal lamina-independent form of laminin exists in and around the cell bodies and proximal portion of the apical dendrites of CA3 pyramidal neurons of the postnatal hippocampus. To understand the possible function of laminin in axon regeneration within this pathway, we have manipulated laminin synthesis at the mRNA level in a slice culture model of the lesioned mossy system. In this model early postnatal mossy fibers severed near the hilus can regenerate across the lesion and elongate rapidly within strata lucidum and pyramidale. In slice cultures of the postnatal day 4 hippocampus, 2 d before lesion and then continuing for 1-5 d after lesion, translation of the gamma1 chain product of laminin was reduced by using antisense oligodeoxyribonucleotides and DNA enzymes. In the setting of the lesioned organotypic hippocampal slice, astroglial repair of the lesion and overall glial patterning were unperturbed by the antisense or DNA enzyme treatments. However, unlike controls, in the treated, lesioned slices the vast majority of regenerating mossy fibers could not cross the lesion site; those that did were very much shorter than usual, and they took a meandering course. In a recovery experiment in which the DNA enzyme or antisense oligos were washed away, laminin immunoreactivity returned and mossy fiber regeneration resumed. These results demonstrate the critical role of laminin(s) in an axon regeneration model of the CNS.

This review of ECM molecules shows quite clearly the function of the ECM in development but more importantly in the mature CNS after injury. Most of the proteoglycans, especially the large CS-PGs, are able to inhibit neurite outgrowth and in vivo experiments are now in progress to specifically inhibit these important molecules. The nature of growth promoter ECM molecules in the CNS after injury, either within or distant from the injury is now becoming better appreciated and we suggest that the laminin family should be important targets for exploration. Indeed, a better understanding of the interaction of laminin with those ECM components that are inhibitory is a clear goal for the future. Our ultimate aim must be to change the balance of factors at lesion sites to allow the more permissive environment after CNS injury to predominate.