Astrogliosis and Axonal Regeneration

Following central nervous system (CNS) injury, the local biochemical changes trigger astrogliosis around the lesion. A number of molecules, including cytokines, chemokines, neurotrophic factors, their receptors, and several intracellular signaling pathways, contribute to astrogliosis after CNS injury. Reactive astrocytes are characterized by highly expressing a few intermediate filaments, including glial fibrillary acidic protein, nestin, and vimentin. Astrogliosis is a defense response of the CNS to minimize and repair primary damage, but it eventually generates harmful effects due to producing high levels of inhibitory molecules to suppress neuronal elongation and forming potent barriers to axon regeneration. Chondroitin sulfate proteoglycans (CSPGs) are highly upregulated by reactive scars and are particularly potent contributors to the growth-limiting environment in the mature CNS. Surmounting strong inhibition by CSPG-rich scars is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcome inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC, but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed to develop more effective therapies to overcome CSPG-mediated inhibition. Because of their large size and dense negative charges, CSPGs were thought to act by nonspecifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3. If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries.