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

• Project/Area Number: 17K16640
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Mie University
• Principal Investigator: Shiba Masato 三重大学, 医学部附属病院, 講師 (30595682)
• Project Period (FY): 2017-04-01 – 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ガレクチン-3 / くも膜下出血 / 早期脳損傷 / galectin-3 / subarachnoid hemorrhage / early brain injury / modified citrus pectin / マトリセル蛋白 / 脳血管障害学 / くも膜下出血後早期脳損傷

Outline of Final Research Achievements

The aim of this study was to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier (BBB) disruption. Male adult mice underwent sham or filament perforation SAH modeling, followed by an intracerebroventricular injection of vehicle or drug. First, vehicle-treated and MCP-treated mice were assessed by neuroscore, brain water content, Evans blue extravasation, Western blotting, immunostaining. Then, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore, Evans blue extravasation and IgG immunostaining were evaluated. MCP prevented post-SAH BBB disruption by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. R-galectin-3 blocked the neuroprotective effects of MCP. This study suggested galectin-3 would be a novel therapeutic target against early brain injury after SAH.

Academic Significance and Societal Importance of the Research Achievements

くも膜下出血は予後不良な疾患であり、その治療介入可能な予後不良因子として早期脳損傷が挙げられる。しかしその病態の詳細なメカニズムについては未だ明らかとなっておらず、したがって、特異的な治療法も無いのが現状である。ガレクチン-3は種々の組織の細胞内外に存在し、アポトーシスや炎症における信号伝達に関与するとされている。今回ガレクチン-3がSAH後の脳において発現が増加し、様々な細胞内情報伝達機構を通して血液脳関門障害と脳浮腫に関連していることが明らかとなった。本研究の成果は将来ガレクチン-3抑制を介する新たな早期脳損傷に対する治療法の開発へと発展する可能性があると考えられる。

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
  • ISBN: 9783030046149, 9783030046156
  • 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
  • ISBN: 9783030046149, 9783030046156
  • 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
  • ISBN: 9783030046149, 9783030046156
  • 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
  • ISBN: 9783030046149, 9783030046156
  • 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
  • ISBN: 9783030046149, 9783030046156
  • 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 Issue: 1 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
  • ISBN: 9783030046149, 9783030046156
  • 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 Issue: 12 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 Issue: 7 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 Issue: 2 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 Issue: 2 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 Issue: 4 Pages: 381-388
  • DOI: 10.1007/s12975-018-0650-y
  • Peer Reviewed
• [Journal Article] Possible Role of Inflammation and Galectin-3 in Brain Injury after Subarachnoid Hemorrhage. (2018)
  • Author(s): Nishikawa H, Suzuki H.
  • Journal Title: Brain Sci. Volume: 8 Issue: 2 Pages: 30-30
  • DOI: 10.3390/brainsci8020030
  • Peer Reviewed
• [Journal Article] Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage. (2018)
  • Author(s): Suzuki H, Nishikawa H, Kawakita F.
  • Journal Title: Neural Regen Res Volume: 13 Issue: 7 Pages: 1175-1178
  • DOI: 10.4103/1673-5374.235022
  • Peer Reviewed
• [Journal Article] Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3. (2018)
  • Author(s): Nishikawa H, Liu L, Nakano F, Kawakita F, Kanamaru H, Nakatsuka Y, Okada T, Suzuki H.
  • Journal Title: Stroke Volume: 49 Issue: 11 Pages: 2743-2751
  • DOI: 10.1161/strokeaha.118.021757
  • Peer Reviewed
• [Journal Article] Increased Plasma Galectin-3 Preceding the Development of Delayed Cerebral Infarction and Eventual Poor Outcome in Non-Severe Aneurysmal Subarachnoid Hemorrhage (2017)
  • Author(s): Nishikawa Hirofumi、pSEED group、Nakatsuka Yoshinari、Shiba Masato、Kawakita Fumihiro、Fujimoto Masashi、Suzuki Hidenori
  • Journal Title: Transl Stroke Res Volume: 9 Issue: 2 Pages: 110-119
  • DOI: 10.1007/s12975-017-0564-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] くも膜下出血患者における急性期血漿中ガレクチン-3濃度とその意義 (2017)
  • Author(s): 西川拓文、中塚慶徳、川北文博、藤本昌志、芝 真人、鈴木秀謙、pSEEDグループ.
  • Journal Title: 脳血管攣縮 Volume: 33 Pages: 31-34
  • Peer Reviewed
• [Journal Article] Matricellular proteinとくも膜下出血後delayed cerebral ischemia (2017)
  • Author(s): 鈴木秀謙、芝 真人、中塚慶徳、中野芙美、西川拓文、Liu Lei
  • Journal Title: 脳血管攣縮 Volume: 33 Pages: 13-15
  • 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
• [Presentation] マウスくも膜下出血後脳損傷におけるガレクチン- 3の役割 (2018)
  • Author(s): 西川拓文、中野芙美、Liu Lei、中塚慶徳、岡田 健、 芝 真人、鈴木秀謙
  • Organizer: 第34回スパズム・シンポジウム
• [Presentation] The Role Of Galectin-3 In Brain Injuries After Subarachnoid Hemorrhage In Mice (2017)
  • Author(s): Hirofumi Nishikawa, Fumi Nakano, Lei Liu, Yoshinari Nakatsuka, Takeshi Okada, Masato Shiba, Hidenori Suzuki.
  • Organizer: The 14th International Conference on Neurovascular Events after Subarachnoid Hemorrhage
  • Int'l Joint Research
• [Presentation] マウスくも膜下出血後脳損傷におけるガレクチン-3の役割 (2017)
  • Author(s): 西川拓文、中野芙美、Liu Lei、中塚慶徳、岡田 健、 芝 真人、鈴木秀謙
  • Organizer: 第49回日本結合組織学会学術大会
• [Remarks] 三重大学大学院 脳神経外科学の研究実績
  • URL: http://www.medic.mie-u.ac.jp/neurosurgery/research/results/index.html