Targeting Inhibitory Chondroitin Sulfate Proteoglycans to Promote Axonal Regeneration in the Central Nervous System

After spinal cord injury (SCI), axons become severed, and glial cells undergo changes in response to environmental cues, contributing to glial scar formation. Chondroitin Sulfate Proteoglycans (CSPGs) are released during glial scarring and are an underlying mechanism for the inhibitory effects on axonal regeneration in the central nervous system (CNS). This review initially focuses on CSPGs and provides a comprehensive overview of the glial scarring process. In addition to established therapeutic agents, such as chondroitinase ABC (chABC), this review addresses therapeutic approaches that target the interactions between CSPG and its transmembrane receptors on growth cones. These receptors belong to the leukocyte common antigen-related (LAR) phosphatase subfamily and the Nogo family, including protein tyrosine phosphatase sigma (PTPσ), LAR receptors, and Nogo receptor variants. This review then shifts to the efficacy of other therapeutic peptides, such as intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), on the interactions between CSPG and PTPσ and LAR receptors. Likewise, it also evaluates decoys for their effectiveness in obstructing interactions between CSPG and Nogo receptors. Additionally, it extensively discusses the impact of deleting these receptors or utilizing peptides and decoys to counteract the inhibitory effects of CSPG and its transmembrane receptors on axonal regeneration, while acknowledging the limitations of these therapeutics and extending future applications. This review aims to highlight these potential therapeutic avenues targeting CSPG to promote axonal regeneration in the CNS, elucidating their use for future treatment.