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The Journal of Neuroscience, August 1, 2002, 22(15):6570-6577
Rho Signaling Pathway Targeted to Promote Spinal Cord Repair
Pauline Dergham1, Benjamin Ellezam1, Charles Essagian1, Hovsep Avedissian2, William D. Lubell2, and Lisa McKerracher1 Départements de 1 Pathologie et Biologie Cellulaire and 2 Chimie, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
The Rho signaling pathway regulates the cytoskeleton and motility and plays an important role in neuronal growth inhibition. Here we demonstrate that inactivation of Rho or its downstream target Rho-associated kinase (ROK) stimulated neurite growth in primary cells of cortical neurons plated on myelin or chondroitin sulfate proteoglycan substrates. Furthermore, treatment either with C3 transferase (C3) to inactivate Rho or with Y27632 to inhibit ROK was sufficient to stimulate axon regeneration and recovery of hindlimb function after spinal cord injury (SCI) in adult mice. Injured mice were treated with a single injection of Rho or Rho-associated kinase inhibitors delivered in a protein adhesive at the lesion site. Treated animals showed long-distance regeneration of anterogradely labeled corticospinal axons and increased levels of GAP-43 mRNA in the motor cortex. Behaviorally, inactivation of Rho pathway induced rapid recovery of locomotion and progressive recuperation of forelimb-hindlimb coordination. These findings provide evidence that the Rho signaling pathway is a potential target for therapeutic interventions after spinal cord injury.
Key words: Rho GTPase; Rho-associated kinase; C3; Y27632; corticospinal tract; regeneration; BBB behavior scale; GAP-43; mouse
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156570-08$05.00/0
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