This chapter outlines some of the various components which may contribute to the observed lack of regeneration which occurs after injury to the adult mammalian central nervous system (CNS). To date, three major inhibitors of axonal regeneration associated with myelin have been identified: myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp). The myelin-associated inhibitors all appear to be present in undamaged myelin and may have roles other than the block of regeneration or inadvertent sprouting. Following the binding of each of the myelin-associated inhibitors to the NgR-p75NTR-LINGO receptor complex, there is an induction of a signaling pathway which eventually leads to the blockage of neurite extension from damaged or naïve adult neurons. If the binding or signaling of a single receptor complex can be compromised, it may be possible to permit sufficient regeneration in the adult mammalian CNS after injury, particularly prior to formation of the glial scar.

This chapter discusses the environment of the glial scar, with particular focus on the role of chondroitin sulfate proteoglycans (CSPGs) in regeneration failure. Many injuries of the central nervous system (CNS) occur with an accompanying opening of the blood-brain barrier. Non-CNS molecules entering the brain parenchyma through the disrupted blood-brain barrier have significant effects on the immune system and subsequent development of the glial scar. It should be reiterated that following injury in the vicinity of blood-brain barrier extravasation, much of the glial scar forms without astrocyte proliferation, but rather with a switch to the reactive state followed by inhibitory extracellular matrix (ECM) production and then hypertrophy. The growth inhibitory and growth promoting molecules exist in a balance that favors stalled regeneration of axons, but it is important to reiterate that non-regenerating axons still need to be supported if they are to remain indefinitely in the vicinity of the lesion.