title: Rho-ROCK inhibition in the treatment of spinal cord injury.
abstract: BACKGROUND
  The Rho pathway has been shown to have a role in the pathophysiology of spinal cord injury (SCI). Upregulation of the Rho signaling pathway occurs as a result of SCI. Activation of Rho and its downstream effector kinases triggers growth cone collapse and represents a significant barrier to axon regeneration. Furthermore, there is evidence that Rho-ROCK signaling mediates the inhibitory effects of chondroitin sulfate proteoglycans on neurons, and that inhibition of Rho and ROCK can reverse chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth. Work building on these findings suggests that inhibition of this pathway may boost neuroprotection and axonal regeneration after SCI.
  
  
  METHODS
  A narrative review.
  
  
  RESULTS
  Investigators have identified a C3 transferase, which selectively inhibits Rho without affecting other guanine triphosphatases. This has been shown to promote axonal sprouting and recovery of locomotor function after hemisection of the thoracic spinal cord in a mouse model of SCI. The neuroprotective properties of Rho inhibitors in animal models of SCI have been reinforced by studies carried out in vitro using retinal ganglion cells. In light of this, a Rho inhibitor known as Cethrin has been evaluated as a therapeutic intervention for SCI in a phase I/IIa clinical trial with promising results.
  
  
  CONCLUSIONS
  The Rho pathway has been shown to have a role in the pathophysiology of SCI and preclinical and clinical work and is currently a promising target for the treatment of patients with SCI.
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Forgione
authors.affiliation: Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: Michael.Fehlings@uhn.on.ca.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D036002:ADP Ribose Transferases / Q000627:therapeutic use; D000818:Animals; D001905:Botulinum Toxins / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D054460:rho-Associated Kinases; D001905:Botulinum Toxins
keywords: Mechanisms of action; Rho inhibition; Rho-ROCK inhibition; Spinal cord injury; Treatment