Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation

Following spinal cord injury (SCI), the adult mammalian nervous system struggles to regenerate synaptic connections due to inherent limitations, growth-inhibiting factors, and insufficient growth factors. The injury triggers immune, inflammatory, and apoptotic events, leading to the release of myelin-associated inhibitors and chondroitin sulfate proteoglycans (CSPGs). A "scar" forms at the injury site, sealing damaged tissue and creating an astrocytic border that minimizes secondary injury. However, myelin-associated inhibitors and CSPGs compromise post-SCI tissue repair by inhibiting axonal regeneration, ultimately blocking the regeneration of damaged circuits. SCI results in alterations in sensory, motor, and autonomic function, severely affecting the quality of life. The interruption of neuronal tracts and the development of alternative circuits can result in compensatory but sometimes erroneous plasticity, leading to events such as pain or bladder dysfunction.

• 1
  Myelin-associated inhibitors like Nogo-A, MAG, and OMgp block neurite outgrowth by binding to receptors like NgR1, Pir-B, and others, initiating downstream signaling pathways like RhoA/ROCK, which leads to actin depolymerization and regeneration failure.
• 2
  CSPGs, synthesized by astrocytes, neurons, OPCs, and macrophages, are upregulated after CNS injury, inhibiting neurite outgrowth by activating receptors like RPTPσ, LAR, NgR1, and NgR3.
• 3
  RGMa, present in myelin and the glial scar, inhibits neurite outgrowth by binding to its neuronal receptor, neogenin. Blocking RGMa promotes regeneration, plasticity, and recovery following SCI in various animal models.