title: Inhibition of Rho-kinase differentially affects axon regeneration of peripheral motor and sensory nerves.
abstract: The small GTPase RhoA and its down-stream effector Rho-kinase (ROCK) are important effector molecules of the neuronal cytoskeleton. Modulation of the RhoA/ROCK pathway has been shown to promote axonal regeneration, however in vitro and animal studies are inconsistent regarding the extent of axonal outgrowth induced by pharmacological inhibition of ROCK. We hypothesized that injury to sensory and motor nerves result in diverse activation levels of RhoA, which may impact the response of those nerve fiber modalities to ROCK inhibition. We therefore examined the effects of Y-27632, a chemical ROCK inhibitor, on the axonal outgrowth of peripheral sensory and motor neurons grown in the presence of growth-inhibiting chondroitin sulfate proteoglycans (CSPGs). In addition we examined the effects of three different doses of Y-27632 on nerve regeneration of motor and sensory nerves in animal models of peripheral nerve crush. In vitro, sensory neurons were less responsive to Y-27632 compared to motor neurons in a non-growth permissive environment. These differences were associated with altered expression and activation of RhoA in sensory and motor axons. In vivo, systemic treatment with high doses of Y-27632 significantly enhanced the regeneration of motor axons over short distances, while the regeneration of sensory fibers remained largely unchanged. Our results support the concept that in a growth non-permissive environment, the regenerative capacity of sensory and motor axons is differentially affected by the RhoA/ROCK pathway, with motor neurons being more responsive compared to sensory. Future treatments, that are aimed to modulate RhoA activity, should consider this functional diversity.
authors.affiliation: Department of Neurology, University of Cologne, Germany; Center for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Abhijeet R
authors.initials: AR
authors.lastname: Joshi
authors.affiliation: Department of Neurology, University of Cologne, Germany; Center for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Bobylev
authors.affiliation: Department of Neurology, University of Texas Health Sciences Centre, Houston, TX, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Texas Health Sciences Centre, Houston, TX, USA.
authors.forename: Kazim A
authors.initials: KA
authors.lastname: Sheikh
authors.affiliation: Department of Neurology, University of Cologne, Germany; Center for Molecular Medicine Cologne, Cologne, Germany. Electronic address: helmar.lehmann@uk-koeln.de.
authors.forename: Helmar C
authors.initials: HC
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology; D015153:Blotting, Western; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000201:enzymology*; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000201:enzymology*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Cytoskeleton; Nerve injury; Regeneration; Remyelination