Enoxaparin promotes functional recovery after spinal cord injury by

The receptor-type protein tyrosine phosphatase sigma (PTPR sigma) regulates axonal regeneration/sprouting as a molecular switch in response to glycan ligands. Cell surface heparan sulfate oligomerizes PTPR sigma and inactivates its enzymatic activity, which in turn promotes axonal growth. In contrast, matrix-associated chondroitin sulfate monomerizes PTPR sigma and activates it. This leads to dephosphorylation of its specific substrates, such as cortactin, resulting in a failure of axonal regeneration after injury. However, this molecular switch model has never been challenged in a clinical situation. In this study, we demonstrated that enoxaparin, a globally approved anticoagulant consisting of heparin oligosaccharides with an average molecular weight of 45 kDa, induced clustering and inactivated PTPR sigma in vitro. Enoxaparin induced PTPR sigma clustering, and counteracted PTPR sigma-mediated dephosphorylation of cortactin, which was shown to be important for inhibition of axonal regeneration. Systemic administration of enoxaparin promoted anatomical recovery after both optic nerve and spinal cord injuries in rats at clinically tolerated doses. Moreover, enoxaparin promoted recovery of motor function without obvious hemorrhage. Collectively, our data provide a new strategy for the treatment of traumatic axonal injury.