title: Enhancement of sciatic nerve regeneration by adenovirus-mediated expression of dominant negative RhoA and Rac1.
abstract: It is known that Rho family small GTPases activate a number of signal transduction pathways involved in cell cycle progression, gene expression, and cell survival. These small G proteins play an important role in neuronal survival and axon regeneration in neural injury. In this study, we tested whether the activity of RhoA or Rac1 regulates neurite extension in dorsal root ganglia (DRGs) in vitro and nerve regeneration in injured sciatic nerves. Regeneration of neurites from explanted DRGs was accelerated by combined suppression of RhoA and Rac1 activity using adenoviruses expressing dominant negative (DN) forms of both RhoA and Rac1 (Ad-Rho/RacDN) in vitro. Rat sciatic nerves were cut and Ad-Rho/RacDN was injected into the proximal stumps. After bridge grafting with chitosan mesh tubes, muscle evoked potentials induced by transcranial electrical stimulation were recorded eight weeks postoperatively. The terminal latencies were shorter in the Ad-Rho/RacDN group than in the control group. Histological analysis revealed extensive regrowth of neurofilament-positive and myelinated axons within the tubes in the group that received Ad-Rho/RacDN. These findings suggest that combined regulation of RhoA and Rac1 using DN adenoviral transgenic methods has the potential to modify injured peripheral nerve tissues directly.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan. kusano.orth@tmd.ac.jp
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kusano
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Enomoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Soichiro
authors.initials: S
authors.lastname: Itoh
authors.forename: Shizuko
authors.initials: S
authors.lastname: Ichinose
authors.forename: Shigeo
authors.initials: S
authors.lastname: Okabe
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shinomiya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000502:physiology; D005822:Genetic Vectors / Q000008:administration & dosage; D009410:Nerve Degeneration / Q000628:therapy*; D009416:Nerve Regeneration; D016501:Neurites / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries / Q000473:pathology* / Q000502:physiology*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins