Development of novel treatment and prognostic prediction for acute brain injury after aneurysmal subarachnoid hemorrhage.

• Project/Area Number: 18K16566
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Yokohama City University
• Principal Investigator: Takase Hajime 横浜市立大学, 医学研究科, 客員研究員 (00549975)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: くも膜下出血 / 急性期脳損傷 / 分子メカニズム / 血管内皮 / 神経炎症 / ミクログリア / cell-cell interaction / translational study / 接着結合

Outline of Final Research Achievements

We investigated the role of soluble vascular-endothelial (sVE) cadherin in aneurysmal subarachnoid hemorrhage (aSAH) that the inflammatory mechanism is strongly associated with the pathophysiology. The clinical part of our reverse-translational study demonstrated that CSF level of sVE-cadherin was negatively correlated with clinical outcome of aSAH patients. Additionally, the experimental part showed that sVE-cadherin activated an inflammatory cascade in microglia. These findings support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.

Academic Significance and Societal Importance of the Research Achievements

本研究において、くも膜下出血における血管内皮細胞由来分子ーミクログリアの新たなcell-cell interactionと、新たな神経炎症分子メカニズムの存在が示唆された。血管内皮の代謝分子VE-cadherinが、血液脳関門の恒常性維持という本来の役割にとどまらず、中枢神経系の炎症において新たな生物学的な機能を有することを示した点で、学術的意義も大きいと考えられる。これらの知見を他の中枢神経疾患に応用することで、新たな研究展開が可能であり、将来の治療開発を通して世界の社会福祉に大きく貢献できる可能性がある。

Research Products

• [Int'l Joint Research] Massachusetts General Hospital/Harvard Medical School/Brigham and Women's Hospital(米国)
• [Int'l Joint Research] マサチューセッツ総合病院・ハーバード大学/ピッツバーグ大学メディカルセンター(米国)
• [Journal Article] Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage. (2020)
  • Author(s): Takase H, Chou SH, Hamanaka G, Ohtomo R, Islam MR, Lee JW, Hsu L, Mathew J, Reyes-Bricio E, Hayakawa K, Xing C, Ning MM, Wang X, Arai K, Lo EH, Lok J.
  • Journal Title: Neurology Volume: 94(12) Issue: 12
  • DOI: 10.1212/wnl.0000000000008868
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microglial responses after phagocytosis: Escherichia coli bioparticles, but not cell debris or amyloid beta, induce matrix metalloproteinase-9 secretion in cultured rat primary microglial cells. (2020)
  • Author(s): Hamanaka G, Kubo T, Ohtomo R, Takase H, Reyes-Bricio E, Oribe S, Osumi N, Lok J, Lo EH, Arai K.
  • Journal Title: Glia Volume: 68(7) Issue: 7 Pages: 1435-1444
  • DOI: 10.1002/glia.23791
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Axonal regeneration and functional recovery driven by endogeneous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy. (2020)
  • Author(s): Ueno, R., Takase, H., Suenaga, J., Kishimoto, M., Kurihara, Y., Takei, K., Kawahara, N., and Yamamoto
  • Journal Title: Experimental Neurology Volume: 323 Pages: 113068-113068
  • DOI: 10.1016/j.expneurol.2019.113068
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translating concepts of neural repair after stroke: Structural and functional targets for recovery. (2020)
  • Author(s): Regenhardt RW, Takase H, Lo EH, Lin DJ.
  • Journal Title: Restorative Neurology and Neuroscience Volume: 38(1) Issue: 1 Pages: 67-92
  • DOI: 10.3233/rnn-190978
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thiel's embalming method with additional intra-cerebral ventricular formalin injection (TEIF) for cadaver training of head and brain surgery. (2020)
  • Author(s): Miyake S, Suenaga J, Miyazaki R, Sasame J, Akimoto T, Tanaka T, Ohtake M, Takase H, Tateishi K, Shimizu N, Murata H, Funakoshi K, Yamamoto T.
  • Journal Title: Anatomical Science International Volume: N/A Issue: 4 Pages: 564-570
  • DOI: 10.1007/s12565-020-00545-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treadmill Exercise Suppresses Cognitive Decline and Increases White Matter Oligodendrocyte Precursor Cells in a Mouse Model of Prolonged Cerebral Hypoperfusion. (2020)
  • Author(s): Ohtomo R, Kinoshita K, Ohtomo G, Takase H, Hamanaka G, Washida K, Islam MR, Wrann CD, Katsuki H, Iwata A, Lok J, Lo EH, Arai K.
  • Journal Title: Transl Stroke Res. Volume: － Issue: 3 Pages: 496-502
  • DOI: 10.1007/s12975-019-00734-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oxidative Stress-Responsive Apoptosis Inducing Protein (ORAIP) Plays a Critical Role in Cerebral Ischemia/Reperfusion Injury (2019)
  • Author(s): Kishimoto M, Suenaga J, Takase H, Araki K, Yao T, Fujimura T, Murayama K, Okumura K, Ueno R, Shimizu N, Kawahara N, Yamamoto T, Seko Y.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 13512-13512
  • DOI: 10.1038/s41598-019-50073-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 進行性の認知機能低下を来している高齢者の脳出血 (2019)
  • Author(s): 大友亮、高瀬創
  • Journal Title: 内科 Volume: 4 Pages: 843-844
  • Peer Reviewed
• [Journal Article] Delayed C5 Palsy After Anterior Cervical Decompression Surgery: Preoperative Foraminal Stenosis and Postoperative Spinal Cord Shift Increase the Risk of Palsy (2018)
  • Author(s): Takase H, Murata H, Sato M, Tanaka T, Miyazaki R, Yoshizumi T, Tateishi K, Kawahara N, Yamamoto T
  • Journal Title: World Neurosurgery Volume: 50(18) Pages: 8732049-7
  • Peer Reviewed
• [Journal Article] Protective effects of a radical scavenger edaravone on oligodendrocyte precursor cells against oxidative stress. (2018)
  • Author(s): Takase H, Liang AC, Miyamoto N, Hamanaka G, Ohtomo R, Maki T, Pham LD, Lok J, Lo EH, Arai K.
  • Journal Title: Neurosci Letters Volume: 6;668 Pages: 120-125
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A radical scavenger edaravone and oligodendrocyte protection/regeneration. (2018)
  • Author(s): Takase H, Lok J, Arai K.
  • Journal Title: Neural Regen Res. Volume: 13(9) Pages: 1550-1551
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] White-matter repair: Interaction between oligodendrocytes and the neurovascular unit (2018)
  • Author(s): Hamanaka G, Ohtomo R, Takase H, Lok J, Arai K
  • Journal Title: Brain Circulation Volume: 4 (3) Pages: 118-123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of oligodendrocyte-neurovascular unit in white matter repair. (2018)
  • Author(s): Hamanaka G, Ohtomo R, Takase H, Lok J, Arai K.
  • Journal Title: Neurosci Lett. Volume: 25;684 Pages: 175-180
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Three-dimensional multimodality fusion imaging as an educational and planning tool for deep-seated meningiomas. (2018)
  • Author(s): Sato M, Tateishi K, Murata H, Kin T, Suenaga J, Takase H, Yoneyama T, Nishii T, Tateishi U, Yamamoto T, Saito N, Inoue T, Kawahara N.
  • Journal Title: Br J Neurosurg. Volume: 26 Pages: 1-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 「ボストン日本人脳外科医の会」便り (2018)
  • Author(s): 伊藤博崇、北村洋平、清川樹里、五味正憲、杉本至健、高瀬創、 千田光平、長嶋宏明、原岡怜、柳澤毅、 Emiri T. Mandeville、脇本浩明
  • Journal Title: 脳神経外科速報 Volume: 8 Pages: 818-822
• [Presentation] White matter damage and microglial alterations after concussive brain injury. (2019)
  • Author(s): Takase H, Ohtomo R, Wang X, Lo EH, Chung JY, Whalen MJ, Arai K, Lok J
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Treadmill exercise suppresses cognitive decline and increases white matter oligodendrocyte precursor cells in a mouse model of prolonged cerebral hypoperfusion (2019)
  • Author(s): Ohtomo R, Ohtomo G, Takase H, Hamanaka G, Iwata A, Lok J, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Biphasic roles of pentraxin 3 in cerebrovascular responses after white matter stroke (2019)
  • Author(s): Shindo A, Ohtomo R, Takase H, Hamanaka G, Maki T, Egawa N, Lok J, Tomimoto H, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Microglial responses after phagocytosis: e. coli bioparticles, but not cell debris or amyloid beta, induce matrix metalloproteinase-9 secretion in vitro (2019)
  • Author(s): Hamanaka G, Ohtomo R, Takase H, Lok J, Lo EH, Arai K
  • Organizer: BRAIN 2019
  • Int'l Joint Research
• [Presentation] Oligodendrocyte injury in concussive brain injury (2018)
  • Author(s): Takase H, Chung JY, Wu L, Wang X, Lo EH, Whalen MJ, Arai K, Lok J
  • Organizer: Neurotrauma 2018
  • Int'l Joint Research
• [Presentation] Soluble VE-cadherin is elevated in CSF in Subarachnoid Hemorrhage (2018)
  • Author(s): Takase H, Chou SH, Arai K, Lo EH, Lok J
  • Organizer: 10th Annual MGHfC Research Day
  • Int'l Joint Research