Enhancement of sciatic nerve regeneration by adenovirus-mediated expression of dominant negative RhoA and Rac1 |
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Authors: | Kusano Kazuo Enomoto Mitsuhiro Hirai Takashi Wakabayashi Yoshiaki Itoh Soichiro Ichinose Shizuko Okabe Shigeo Shinomiya Kenichi Okawa Atsushi |
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Institution: | Department of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan. kusano.orth@tmd.ac.jp |
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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. |
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Keywords: | Ads adenoviruses DRG dorsal root ganglia DN dominant negative CNS central nervous system NGF nerve growth factor GFP green fluorescent protein IRES internal ribosome entry site Tuj1 β-tubulin III MEP muscle evoked potential NF neurofilament |
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