Molecular biological mechanism underlying improvement of functional recovery after the exercise therapy combined with the electrical stimulation of injured spinal cord

• Project/Area Number: 19K18515
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kyushu University (2021); Japan Organization of Occupational Health and Safety, Spinal Injuries Center (2019-2020)
• Principal Investigator: Kobayakawa Kazu 九州大学, 大学病院, 助教 (40772322)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脊髄損傷 / 電気刺激 / リハビリテーション / シナプス / 脊髄電気刺激

Outline of Research at the Start

先行研究（Kobayakawa et al., Neurorehabilitation and Neural Repair, 2019）において、トレーニングだけでも損傷脊髄の腰髄におけるシナプスに変化を与え得る事を明らかにし、今回の解析手法によって治療が与える影響のメカニズムを探索する事が可能である事を示した。今後は同様のプロトコルで「脊髄電気刺激のみ」と「脊髄電気刺激併用トレーニング」の遺伝子発現における効果をRNA-Seqで網羅的に解析する事によって、脊髄電気刺激による治療効果のメカニズムを解明する。

Outline of Final Research Achievements

The effects of electrostimulation (ES) of lumbar spinal cord or the combined use of ES and training were analyzed by using RNA-Seq. The expression of genes related to GO-term such as positive regulation of neuron differentiation or positive regulation of neurogenesis was significantly increased by single ES after hemisection of the spinal cord. When ES and training were used in combination for one week after spinal cord hemisection, the expression of genes related to GO-term such as neuron projection development, axonogenesis, synapse and myelination was increased, which suggests promotion of axon and myelin regeneration.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、脊髄損傷後の脊髄電気刺激自体に脊髄内在性神経幹細胞のニューロンへの分化を促し、アストログリオーシスを軽減する効果がある事が示唆された。また、組織学的にも電気刺激によってシナプス蛋白増加が起きる事が確認された。本研究成果は脊髄電気刺激と四肢トレーニングの併用が神経回路再構築を介して、脊髄損傷の運動機能回復を促進する可能性を示している。

Research Products

• [Journal Article] 特集 脊髄損傷の治療アップデート 脊髄損傷急性期の血糖管理の重要性-機能予後改善の観点から- (2022)
  • Author(s): 小早川 和、幸 博和、岡田 誠司、河野 修、前田 健、中島 康晴
  • Journal Title: 関節外科 基礎と臨床 Volume: 41 Issue: 3 Pages: 289-293
  • DOI: 10.18885/JJS.0000000921
  • ISSN: 0286-5394
  • Year and Date: 2022-03-19
• [Journal Article] Incidence and risk factors of pneumonia following acute traumatic cervical spinal cord injury (2022)
  • Author(s): Hayashi Tetsuo、Fujiwara Yuichi、Kawano Osamu、Yamamoto Yuzo、Kubota Kensuke、Sakai Hiroaki、Masuda Muneaki、Morishita Yuichiro、Kobayakawa Kazu、Yokota Kazuya、Kaneyama Hironari、Maeda Takeshi
  • Journal Title: The Journal of Spinal Cord Medicine Volume: 2 Issue: 5 Pages: 1-7
  • DOI: 10.1080/10790268.2022.2027323
  • Peer Reviewed
• [Journal Article] Epidural Fat Tissue is More Effective for Scar Prevention Than Conventional Subcutaneous Fat Grafting After Laminectomy in a Mouse Model (2021)
  • Author(s): Hata Kazuhiro、Kobayakawa Kazu、Saiwai Hirokazu、Tamaru Tetsuya、Iura Hirotaka、Haruta Yohei、Ono Gentarou、Kitade Kazuki、Maeda Takeshi、Nakashima Yasuharu、Okada Seiji
  • Journal Title: Spine Volume: Publish Ahead of Print Issue: 11 Pages: E485-E493
  • DOI: 10.1097/brs.0000000000004281
  • Peer Reviewed
• [Journal Article] Significance of the neurological level of injury as a prognostic predictor for motor complete cervical spinal cord injury patients (2021)
  • Author(s): Kawano Osamu、Maeda Takeshi、Sakai Hiroaki、Masuda Muneaki、Morishita Yuichiro、Hayashi Tetsuo、Kubota Kensuke、Kobayakawa Kazu、Yokota Kazuya、Kaneyama Hironari
  • Journal Title: The Journal of Spinal Cord Medicine Volume: 8 Issue: 3 Pages: 1-7
  • DOI: 10.1080/10790268.2021.1903139
  • Peer Reviewed
• [Journal Article] Long-term outcomes of spinal meningioma resection with outer layer of dura preservation technique (2021)
  • Author(s): Saiwai Hirokazu、Okada Seiji、Hayashida Mitsumasa、Harimaya Katsumi、Matsumoto Yoshihiro、Kawaguchi Ken-ichi、Iida Kei-ichiro、Kobayakawa Kazu、Yokota Kazuya、Maeda Takeshi、Tsuchiya Kuniyoshi、Arizono Takeshi、Saito Taichi、Nakaie Kazutoshi、Iwamoto Yukihide、Nakashima Yasuharu
  • Journal Title: Journal of Clinical Neuroscience Volume: 83 Pages: 68-70
  • DOI: 10.1016/j.jocn.2020.11.026
  • Peer Reviewed
• [Journal Article] How much time is necessary to confirm the diagnosis of permanent complete cervical spinal cord injury? (2020)
  • Author(s): Kawano Osamu、Maeda Takeshi、Mori Eiji、Takao Tsuneaki、Sakai Hiroaki、Masuda Muneaki、Morishita Yuichiro、Hayashi Tetsuo、Kubota Kensuke、Kobayakawa Kazu、Kaneyama Hironari
  • Journal Title: Spinal Cord Volume: 58 Issue: 3 Pages: 284-289
  • DOI: 10.1038/s41393-019-0366-1
  • Peer Reviewed
• [Journal Article] Macrophage centripetal migration drives spontaneous healing process after spinal cord injury (2019)
  • Author(s): Kobayakawa K、Ohkawa Y、 Yoshizaki S、T、Saito T、Kijima Ken、Yokota K、Hara M、Kubota K、Matsumoto Y、Harimaya K、Ozato K、Masuda T、Tsuda M、Tamura T、Inoue K、Edgerton V. R、Iwamoto Y、Nakashima Y、Okada S
  • Journal Title: Science Advances Volume: 5 Issue: 5
  • DOI: 10.1126/sciadv.aav5086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Locomotor Training Increases Synaptic Structure With High NGL-2 Expression After Spinal Cord Hemisection (2019)
  • Author(s): Kobayakawa Kazu、DePetro Kyleigh Alexis、Zhong Hui、Pham Bau、Hara Masamitsu、Harada Akihito、Nogami Jumpei、Ohkawa Yasuyuki、Edgerton V. Reggie
  • Journal Title: Neurorehabilitation and Neural Repair Volume: 33 Issue: 3 Pages: 225-231
  • DOI: 10.1177/1545968319829456
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A method for predicting the location of dural attachment of spinal meningioma: tumor attachment angle (2021)
  • Author(s): Kobayakawa K, Maeda T, Kawano O, Sakai H, Masuda M, Morishita Y, Hayashi T, Kubota K, Yokota K, Kaneyama H, Saiwai H, Iida K, Matsushita A, Kawaguchi K, Matsumoto Y, Nakashima Y
  • Organizer: 13th Combined meeting of Asia Pacific Spine Society & Asia Pacific Orthopaedic Society
  • Int'l Joint Research
• [Presentation] 脊髄損傷の病態解明と新規治療法の開発 (2021)
  • Author(s): 小早川 和, 岡田 誠司, 幸 博和, 田丸 哲弥, 井浦 広貴, 春田 陽平, 小野 玄太郎, 北出 一季, 前田 健, 中島 康晴
  • Organizer: 第56回日本脊髄障害医学会
• [Presentation] IRF8を介した末梢血単球由来マクロファージの脊髄内求心性遊走は脊髄損傷後の運動機能回復を促進する (2021)
  • Author(s): 小早川和, 岡田誠司, 久保田健介, 松本嘉寛, 中島康晴, 横田和也, 林哲生, 森下雄一郎, 益田宗彰, 播广谷 勝三, 坂井宏旭, 河野修, 前田健
  • Organizer: 第50回日本脊椎脊髄病学会学術集会
• [Presentation] 末梢血由来マクロファージの脊髄内求心性遊走は脊髄損傷後の自然回復過程を促進する (2020)
  • Author(s): 小早川 和
  • Organizer: 第93回日本整形外科学会学術総会
• [Presentation] Tumor Attachment Angle: A new method for predicting dural attachment location of spinal meningioma (2020)
  • Author(s): 小早川 和
  • Organizer: 第49回日本脊椎脊髄病学会学術集会
• [Presentation] Interactive centripetal migration of macrophages and astrocytes enhances spontaneous recovery after spinal cord injury (2020)
  • Author(s): 小早川 和
  • Organizer: 第49回日本脊椎脊髄病学会学術集会
• [Presentation] Centripetal migration of infiltrating macrophage drives spontaneous healing process after spinal cord injury (2020)
  • Author(s): Kazu Kobayakawa
  • Organizer: ORS2020
  • Int'l Joint Research
• [Presentation] Locomotor Training Increases NGL-2-positive Synaptic Structure After Spinal Cord Hemisection (2019)
  • Author(s): Kazu Kobayakawa
  • Organizer: ISCOS2019
  • Int'l Joint Research
• [Presentation] マクロファージの求心性遊走は脊髄損傷後の自発的な治癒過程を促進する (2019)
  • Author(s): 小早川 和
  • Organizer: 第54回日本脊髄障害医学会