一般口演
運動障害 / 脳外傷とトラウマなど
Movement Disorders / Brain Injury and Trauma
座長：武内 恒成（愛知医科大学 医学部） |
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| 2022年7月3日 10:00～10:15 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m2-01
脊髄損傷後の運動機能回復における上昇した脊髄のアウトプットは、運動野神経細胞活動の変化と関連する
Enhanced spinal outputs are associated with compensatory changes in cell activities of monkey motor cortex through motor recovery after spinal cord injury
*兼重 美希(1)、尾原 圭(1,2)、鈴木 迪諒(1)、田添 歳樹(1)、西村 幸男(1)
1. 東京都医学総合研究所、2. 新潟大学大学院 医歯薬総合研究科
*Miki Kaneshige(1), Kei Obara(1,2), Michiaki Suzuki(1), Toshiki Tazoe(1), Yukio Nishimura(1)
1. Tokyo Metropolitan Institute of Medical Science, 2. Graduate School of Medical and Dental Sciences, Niigata University
Keyword: movement, functional recovery, motor cortex, spinal cord
Individuals with injury of descending pathways exhibit motor deficits. Rehabilitation engages residual neural circuits in recovering the motor function after the injury. Brain imaging studies demonstrated that during recovery process after spinal cord injury (SCI), activity in motor-related areas increased and the recruited cortical areas changed progressively. In addition, electrophysiological studies showed that after SCI, somatotopical mapping changed in the spinal cord as well as in the primary motor cortex (M1). These previous results imply that plastic change in the M1 is associated with plastic change in the spinal cord. However, it remains unclear how M1 cell activities relate to spinal motor outputs during the recovery course. Here, we examined the single cell activities in the M1 and the spinal motor outputs throughout the recovery course in a monkey with SCI at the border of C4 and C5. After SCI, the monkey was able to produce weak muscle activities which were not enough to perform a wrist motor task. To facilitate functional recovery, the monkey trained on the motor task with activity-dependent stimulation which is muscle-controlled spinal stimulation to the cervical enlargement below the lesion. Electrical stimulation produced muscle activities in wrist and finger muscles and wrist torques on a paretic hand. The task performance without spinal stimulation improved day by day. Through the course of motor recovery, the spinal motor outputs, assessed at rest prior to each day’s experiment, were also gradually enhanced. In contrast, we found the gradual decreases in the modulation of single cell activities in the contralesional M1 during the task without electrical stimulation. Our results indicate that motor recovery by the rehabilitation combined with activity-dependent stimulation accompanies the activity changes in both of cortical and spinal levels. Plastically enhanced spinal outputs may lead to compensatory decreases in M1 cell activities after SCI. | | 2022年7月3日 10:15～10:30 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m2-02
人為的シナプスコネクトと神経再生環境場整備による後期脊髄損傷からの回復
The recovery from the late-phase of Spinal Cord Injury by synapse connect and environmental improvement for neural regeneration
*笹倉 寛之(1)、鈴木 邦道(2)、池野 正史(1)、森岡 幸(1)、武内 由佳(1)、柚崎 通介(2)、武内 恒成(1)
1. 愛知医科大学、2. 慶應義塾大学
*Hiroyuki Sasakura(1), Kunimichi Suzuki(2), Masashi Ikeno(1), Yuki Morioka(1), Yuka Takeuchi(1), Michisuke Yuzaki(2), Kosei Takeuchi(1)
1. Aichi Medical University, School of Medicine, 2. Keio University, School of Medicine
Keyword: Spinal cord injury(SCI), Artificial synapse connect, Synapse connector, neural regeneration
Spinal cord injury(SCI) causes permanent dysfunction in the body movement and sensation. It is well known that recovery becomes more difficult as time passes from injury. Even with the power of stem cell transplant, it is still hard to cure the late phase of SCI. Despite the difficulty, majority of patients suffering from SCI are clinically late phase. Thus, overcoming the late phase of SCI is an important mission. CPTX is the structurally guided synthetic peptide that joins the pre-synaptic neurexin and the post-synaptic AMPA receptors(Suzuki, Sasakura et al., Science, 2020). We previously showed that CPTX recovered the early phase of SCI in mouse model. CPTX restored the behavioral deficiency of Ataxia and Alzheimer’s mouse model as well. Therefore, CPTX is expected to be a promising medical agent to cure degenerated or injured CNS with novel concept (Salines, Science, 2020). To test if CPTX is effective to the late phase of SCI, we applied CPTX to the mice 4 or 6 weeks after SCI, which correspond to subacute or chronic phase of SCI patients, respectively. CPTX restored the late-phase of SCI. CPTX injection activated the hind leg movement within a few days, which otherwise showed the permanently poor movement. At 2 weeks after injection, the effect of CPTX became maximum to the extent that some animals smoothly stepped. These results suggest that CPTX boost the dormant neural pathway into the active circuit. We are attempting the more robust recovery combined with rehabilitation. The environmental condition surrounding the injured site at the spinal cord is critical for the neural regeneration. Some factors inhibit the neural regeneration. Chondroitin sulphate proteoglycan(CSPG) is one of the most powerful repulsive factors for axon regeneration. We and others previously found that down-regulation of CSPG by enzymatically or genetically promoted the axon regeneration and recovery from SCI(Takeuchi et al., Nat. Commun. 2013). Aiming clinical application, we conducted comprehensive screening of the anti-sense oligos(ASO) and identified the ASOs that inhibit the expression ofGalNAc-T1 gene which is critical for CS biosynthesis(AMED project). The application of these oligos successfully restored the acute phase of SCI. We further found that one of the oligos recovered the subacute phase of SCI(2 weeks after SCI). Since the time window and the mechanism of T1ASO and CPTX for SCI recovery are different, the combination of both strategies would be useful. | | 2022年7月3日 10:30～10:45 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m2-03
DJ-1は脳梗塞後の無菌的炎症を引き起こす新規DAMPである
Extracellular DJ-1 induces sterile inflammation after ischemic stroke
*中村 幸太郎(1,2)、酒井 誠一郎(2)、津山 淳(2)、七田 崇(2)
1. 東京大学大学院 新領域創成科学研究科、2. 東京都医学総合研究所 脳卒中ルネサンスプロジェクト
*Koutarou NAKAMURA(1,2), Seiichiro Sakai(2), Jun Tsuyama(2), Takashi Shichita(2)
1. The University of Tokyo, 2. Stroke Renaissance Project Tokyo Metropolitan Institute of Medical Science
Keyword: Ischemic stroke, Sterile inflammation, DAMPs, Macrophage
-Objective
Post-ischemic inflammation plays a pivotal role in the progression of ischemic stroke pathologies. However, the detailed molecular mechanisms underlying the activation of infiltrating immune cells which trigger sterile post-ischemic inflammation have not been sufficiently clarified. We tried to identify the previously unknown damage-associated molecular patterns (DAMPs), inflammatogenic self-molecules derived from damaged tissue.
-Methods
Among the candidate proteins which were detected from brain lysate by mass spectrometry, recombinant proteins were generated and added to the culture of bone marrow-derived macrophages (BMMs) to examine the expression of inflammatory cytokines. To determine the important peptide sequence for DAMP activity, deletion mutant peptides were generated. We finally examined the extracellular release of candidate DAMPs by using a mouse model of transient middle cerebral artery occlusion (MCAO). Neutralizing antibodies or KO mice were used for compromising DAMP activity in ischemic stroke.
-Results
We successfully identified DJ-1 (Also known as Park7) as a novel DAMP in brain lysate. Recombinant DJ-1 protein activated BMMs only through TLR2 and TLR4. The expression of inflammatory cytokines was induced in a DJ-1 dose-dependent manner in vitro. DJ-1 had a unique peptide sequence, which was not related to its antioxidant activity, to trigger the production of inflammatory cytokines. In the ischemic brain, we observed the induction of DJ-1 expression within only ischemic neuronal cells 6 to 12 hours after stroke onset. Twenty-four hours after stroke onset, DJ-1 was passively released into extracellular space from necrotic brain cells and directly contacted with the surface of infiltrating myeloid cells. DJ-1 deficiency significantly reduced the expression of inflammatory cytokines after the stroke. Administration of DJ-1-neutralizing antibody suppressed the expression of inflammatory cytokines and reduced the infarct volume and improved neurological deficits.
-Conclusion
DJ-1 was released into extracellular space in the ischemic brain and functioned as the previously unknown DAMP that directly activated infiltrating myeloid cells and induced sterile inflammation. Thus, extracellular DJ-1 would be a prominent therapeutic target for ischemic stroke. | | | |
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