Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition

Liang Zhang, Shinjiro Kaneko, Kaoru Kikuchi, Akihiko Sano, Miho Maeda, Akiyoshi Kishino, Shinsuke Shibata, Masahiko Mukaino, Yoshiaki Toyama, Meigen Liu, Toru Kimura, Hideyuki Okano, Masaya Nakamura

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background: Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the "rewiring" of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment. Results: Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles). Conclusions: This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.

Original languageEnglish
Article number14
JournalMolecular brain
Volume7
Issue number1
DOIs
Publication statusPublished - 10-03-2014

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Axons
Recovery of Function
Regeneration
Hindlimb
Spinal Cord Injuries
Central Pattern Generators
Therapeutics
Drug Delivery Systems
Rehabilitation
Muscles
vinaxanthone
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Zhang, L., Kaneko, S., Kikuchi, K., Sano, A., Maeda, M., Kishino, A., ... Nakamura, M. (2014). Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition. Molecular brain, 7(1), [14]. https://doi.org/10.1186/1756-6606-7-14
Zhang, Liang ; Kaneko, Shinjiro ; Kikuchi, Kaoru ; Sano, Akihiko ; Maeda, Miho ; Kishino, Akiyoshi ; Shibata, Shinsuke ; Mukaino, Masahiko ; Toyama, Yoshiaki ; Liu, Meigen ; Kimura, Toru ; Okano, Hideyuki ; Nakamura, Masaya. / Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition. In: Molecular brain. 2014 ; Vol. 7, No. 1.
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abstract = "Background: Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the {"}rewiring{"} of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment. Results: Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles). Conclusions: This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.",
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Zhang, L, Kaneko, S, Kikuchi, K, Sano, A, Maeda, M, Kishino, A, Shibata, S, Mukaino, M, Toyama, Y, Liu, M, Kimura, T, Okano, H & Nakamura, M 2014, 'Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition', Molecular brain, vol. 7, no. 1, 14. https://doi.org/10.1186/1756-6606-7-14

Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition. / Zhang, Liang; Kaneko, Shinjiro; Kikuchi, Kaoru; Sano, Akihiko; Maeda, Miho; Kishino, Akiyoshi; Shibata, Shinsuke; Mukaino, Masahiko; Toyama, Yoshiaki; Liu, Meigen; Kimura, Toru; Okano, Hideyuki; Nakamura, Masaya.

In: Molecular brain, Vol. 7, No. 1, 14, 10.03.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition

AU - Zhang, Liang

AU - Kaneko, Shinjiro

AU - Kikuchi, Kaoru

AU - Sano, Akihiko

AU - Maeda, Miho

AU - Kishino, Akiyoshi

AU - Shibata, Shinsuke

AU - Mukaino, Masahiko

AU - Toyama, Yoshiaki

AU - Liu, Meigen

AU - Kimura, Toru

AU - Okano, Hideyuki

AU - Nakamura, Masaya

PY - 2014/3/10

Y1 - 2014/3/10

N2 - Background: Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the "rewiring" of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment. Results: Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles). Conclusions: This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.

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