Role of galectin-3 for the mechanism of early brain injury after subarachnoid hemorrhage.

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K16640
• Research Institution: Mie University
• Principal Investigator: 芝 真人 三重大学, 医学部附属病院, 講師 (30595682)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: galectin-3 / subarachnoid hemorrhage / early brain injury

Outline of Annual Research Achievements

マトリセル蛋白は細胞外マトリックスに属する蛋白群であるが、それ自体は細胞支持組織としての役割は有さない特殊なもので、正常状態ではほとんど発現しておらず、病的状態で発現が増強し、細胞表面の受容体、サイトカイン、他の細胞外マトリックスなどと反応し、細胞間、細胞とマトリックス間の様々な機能を調節する。ガレクチン-3はマトリセル蛋白の１つで、研究代表者及び研究協力者が行った臨床研究では、脳動脈瘤破裂によるくも膜下出血（SAH）後に血液中で増加することが確認されているが、その意義は未だ明らかになっていない。本研究ではガレクチン-3の早期脳損傷における役割について検討し、そのメカニズムを解明することを目的としている。
2018年度にガレクチン-3のインヒビターであるmodified citrus pectin(MCP)がSAH後の早期脳損傷を抑制（MCPはERK1/2, STAT-3, MMP-9などの細胞内シグナリング関連蛋白を不活化することで、神経症状の悪化、血液脳関門障害とガレクチン-3誘導を抑制した）することを確認した。これに引き続き精製ガレクチン-3を投与する実験を行ったところ、MCPにより抑制されていた血液脳関門障害と神経症状の悪化が認められた。これまでの研究結果から、SAHにより脳内毛細血管内皮細胞からガレクチン-3が発現し、ガレクチン-3がToll様受容体-4に結合してERK1/2, STAT-3などの細胞内シグナリングが活性化し，MMP-9の発現が亢進することで血液脳関門障害が起こり、脳浮腫や神経症状が悪化するというSAH後早期脳損傷の新たなメカニズムを証明できた。今後ガレクチン-3を標的にした治療法の開発に寄与できる可能性が示唆された。

Research Products

• [Journal Article] The Role of Galectin-3 in Subarachnoid Hemorrhage: A Preliminary Study. (2020)
  • Author(s): Nishikawa H, Nakano F, Liu L, Nakatsuka Y, Okada T, Shiba M, Suzuki H
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 65-68
  • DOI: 10.1007/978-3-030-04615-6_11.
  • Peer Reviewed
• [Journal Article] Toll-Like Receptor 4 and Tenascin-C Signaling in Cerebral Vasospasm and Brain Injuries After Subarachnoid Hemorrhage. (2020)
  • Author(s): Suzuki H, Fujimoto M, Kawakita F, Liu L, Nakano F, Nishikawa H, Okada T, Imanaka-Yoshida K, Yoshida T, Shiba M.
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 91-96
  • DOI: 10.1007/978-3-030-04615-6_15
  • Peer Reviewed
• [Journal Article] TAK-242, Toll-Like Receptor 4 Antagonist, Attenuates Brain Edema in Subarachnoid Hemorrhage Mice. (2020)
  • Author(s): Okada T, Lei L, Nishikawa H, Nakano F, Nakatsuka Y, Suzuki H.
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 77-81
  • DOI: 10.1007/978-3-030-04615-6_13.
  • Peer Reviewed
• [Journal Article] Link Between Receptors That Engage in Developing Vasospasm After Subarachnoid Hemorrhage in Mice. (2020)
  • Author(s): Nakano F, Kawakita F, Liu L, Nakatsuka Y, Nishikawa H, Okada T, Shiba M, Suzuki H.
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 55-58
  • DOI: 10.1007/978-3-030-04615-6_9.
  • Peer Reviewed
• [Journal Article] Possible Involvement of Caspase-Independent Pathway in Neuronal Death After Subarachnoid Hemorrhage in Mice. (2020)
  • Author(s): Nakano F, Liu L, Kawakita F, Nakatsuka Y, Nishikawa H, Okada T, Shiba M, Suzuki H.
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 43-46
  • DOI: 10.1007/978-3-030-04615-6_7.
  • Peer Reviewed
• [Journal Article] Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: Findings from basic and clinical studies. (2020)
  • Author(s): Suzuki H, Fujimoto M, Kawakita F, Liu L, Nakatsuka Y, Nakano F, Nishikawa H, Okada T, Kanamaru H, Imanaka-Yoshida K, Yoshida T, Shiba M.
  • Journal Title: J Neurosci Res Volume: 98 Pages: 42-56
  • DOI: 10.1002/jnr.24330.
  • Peer Reviewed
• [Journal Article] Role of Computational Fluid Dynamics for Predicting Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Study Protocol for a Multicenter Prospective Study. (2020)
  • Author(s): Shiba M, Ishida F, Miya F, Araki T, Mase M, Kurita H, Kasuya H, Yamamoto T, Kato Y, Iwabuchi S, Suzuki H; CFD3 Study Group.
  • Journal Title: Acta Neurochir Suppl Volume: 127 Pages: 161-164
  • DOI: 10.1007/978-3-030-04615-6_24.
  • Peer Reviewed
• [Journal Article] Morphological Characteristics of Neuronal Death After Experimental Subarachnoid Hemorrhage in Mice Using Double Immunoenzymatic Technique. (2019)
  • Author(s): Nakano F, Liu L, Kawakita F, Kanamaru H, Nakatsuka Y, Nishikawa H, Okada T, Shiba M, Suzuki H.
  • Journal Title: J Histochem Cytochem Volume: 67 Pages: 919-930
  • DOI: 10.1369/0022155419878181
  • Peer Reviewed
• [Journal Article] Anti-vasospastic Effects of Epidermal Growth Factor Receptor Inhibitors After Subarachnoid Hemorrhage in Mice. (2019)
  • Author(s): Nakano F, Kawakita F, Liu L, Nakatsuka Y, Nishikawa H, Okada T, Kanamaru H, Pak S, Shiba M, Suzuki H.
  • Journal Title: Mol Neurobiol Volume: 56 Pages: 4730-4740
  • DOI: 10.1007/s12035-018-1400-6.
  • Peer Reviewed
• [Journal Article] Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice. (2019)
  • Author(s): Okada T, Kawakita F, Nishikawa H, Nakano F, Liu L, Suzuki H.
  • Journal Title: Mol Neurobiol Volume: 56 Pages: 976-985
  • DOI: 10.1007/s12035-018-1145-2.
  • Peer Reviewed
• [Journal Article] Lessons from tenascin-C knockout mice and potential clinical application to subarachnoid hemorrhage. (2019)
  • Author(s): Shiba M, Suzuki H.
  • Journal Title: Neural Regen Res Volume: 14 Pages: 262-264
  • DOI: 10.4103/1673-5374.244789.
  • Peer Reviewed
• [Journal Article] Dose-Dependent Inhibitory Effects of Cilostazol on Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. (2019)
  • Author(s): Suzuki H, Nakatsuka Y, Yasuda R, Shiba M, Miura Y, Terashima M, Suzuki Y, Hakozaki K, Goto F, Toma N.
  • Journal Title: Transl Stroke Res Volume: 10 Pages: 381-388
  • DOI: 10.1007/s12975-018-0650-y.
  • Peer Reviewed
• [Presentation] Neuroinflammation as a target for intervention in subarachnoid hemorrhage (2019)
  • Author(s): Hidenori Suzuki, Fumihiro Kawakita, Fumi Nakano, Hideki Kanamaru, Masato Shiba
  • Organizer: 5th International Conference on Subarachnoid Hemorrhage、Amsterdam
  • Int'l Joint Research / Invited
• [Presentation] Significance of tenascin-C expression in an acute phase of subarachnoid hemorrhage (2019)
  • Author(s): Fumi Nakano, Hirofumi Nishikawa, Yoshinari Nakatsuka, Fumihiro Kawakita, Hideki Kanamaru, Takeshi Okada, Masato Shiba, Hidenori Suzuki
  • Organizer: 5th International Conference on Subarachnoid Hemorrhage、Amsterdam
  • Int'l Joint Research
• [Presentation] Comparison of prognostic factors between the elderly over age 75 and the non-elderly treated with acute-stage obliteration for ruptured cerebral aneurysm (2019)
  • Author(s): Hideki Kanamaru, Fumihiro Kawakita, Fumi Nakano, Yoichi Miura, Masato Shiba, Ryuta Yasuda, Naoki Toma, Hidenori Suzuki
  • Organizer: 5th International Conference on Subarachnoid Hemorrhage、Amsterdam
  • Int'l Joint Research
• [Presentation] Computatinal fluid dynamics for predicting the recurrence of unruptured cerebral aneurysm after stent-assisted coil embolization (2019)
  • Author(s): Masato Shiba, Fujimaro Ishida, Masanori Tsuji, Hidenori Suzuki
  • Organizer: 5th International Conference on Subarachnoid Hemorrhage、Amsterdam
  • Int'l Joint Research
• [Presentation] Possible role of matricellular protein tenascin-C after subarachnoid hemorrhage: clinical and experimental studies (2019)
  • Author(s): Fumi Nakano, Hirofumi Nishikawa, Yoshinari Nakatsuka, Fumihiro Kawakita, Hideki Kanamaru, Takeshi Okada, Masato Shiba, Hidenori Suzuki
  • Organizer: BRAIN & BRAIN PET 2019、Yokohama
  • Int'l Joint Research