Inflammasome activation induced rupture of intracranial aneurysms

• Project/Area Number: 17K10831
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: TADA Yoshiteru 徳島大学, 病院, 特任講師 (30547964)
• Co-Investigator(Kenkyū-buntansha): 兼松 康久 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (90363142) ; 島田 健司 徳島大学, 病院, 特任講師 (60624351) ; 高麗 雅章 徳島大学, 大学院医歯薬学研究部(医学域), 徳島大学専門研究員 (60794013)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脳 / 脳動脈瘤破裂 / くも膜下出血 / エストロゲン欠乏 / 脳・神経 / inflammasome / 脳動脈瘤 / 薬物治療 / 脳神経疾患 / Inflammasome / 選択的エストロゲン受容体作動薬

Outline of Final Research Achievements

Subarachnoid hemorrhage (SAH) due to rupture of intracranial aneurysms is catastrophic and the prognosis is poor. To study the relationship among IA rupture, estrogen deficiency, and the activation of NLRP3 inflammasomes we used rat IA model and human brain vascular endothelial- and smooth muscle cells (HBEC, HBSMC). The rate of ruptured IAs was higher in ovariectomized hypertensive (OVX+/HT) - than non-ovariectomyzed hypertensive (OVX-/HT) rats (p < 0.05). In OVX+/HT rats, ERα; but not ERβ was reduced and NLRP3 was elevated at the vascular wall prone to rupture, in correlated with an increased mRNA level of NLRP3, IL-β and matrix metallopoteinase-9 and a decrease in the mRNA level of Sirtuin (SIRT1). We confirmed the similar changes in HBEC and HBSMC under the estrogen deficient conditions. The down-regulation of ERα and SIRT1 by estrogen deficient may contribute to the activation of the NLRP3/IL-β/MMP-9 pathway and result in the rupture of intracranial aneurysms.

Academic Significance and Societal Importance of the Research Achievements

脳動脈破裂によるくも膜下出血（SAH）は、予後が重篤で、寝たきり原因の国内第一位である。予防的治療に外科的治療が行われるが、閉経期以後の女性に発症例が多いが、経過観察を行う場合もあり、多角的な原因究明と有効な薬物治療法が切望されている。本研究では治療標的探索のため、動物実験モデルや細胞実験において、エストロゲン欠乏により、inflammasomeが活性化し、炎症関連分子のIL-1βや、血管を構成するマトリックスの崩壊分子MMP-9が高発現し、エストロゲン受容体の制御によりこれらを制御できる可能性を見出した。またこれらの分子の制御が治療標的となる可能性を示唆した。

Research Products

• [Journal Article] Activation of mirror neuron system during gait observation in sub-acute stroke patients and healthy persons (2019)
  • Author(s): Hioka Akemi、Tada Yoshiteru、Kitazato Keiko、Kanematsu Yasuhisa、Mizobuchi Yoshifumi、Mure Hideo、Shimada Kenji、Okazaki Toshiyuki、Korai Masaaki、Akazawa Naoki、Matsumoto Yuki、Harada Masafumi、Takagi Yasushi、Nagahiro Shinji
  • Journal Title: Journal of Clinical Neuroscience Volume: 60 Pages: 79-83
  • DOI: 10.1016/j.jocn.2018.09.035
  • Peer Reviewed / Open Access
• [Journal Article] Time-dependent and site-dependent morphological changes in rupture-prone arteries: ovariectomized rat intracranial aneurysm model (2019)
  • Author(s): Yamaguchi Tadashi、Miyamoto Takeshi、Kitazato Keiko T.、Shikata Eiji、Yamaguchi Izumi、Korai Masaaki、Shimada Kenji、Yagi Kenji、Tada Yoshiteru、Matsuzaki Yoshihito、Kanematsu Yasuhisa、Takagi Yasushi
  • Journal Title: Journal of Neurosurgery Volume: - Pages: 1-9
  • DOI: 10.3171/2019.6.jns19777
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone Pilot Study (2018)
  • Author(s): 1.Nagahiro S, Tada Y, Satomi J, Kinouchi T, Kuwayama K, Yagi K, Nakajima K, Matsushita N, Miyamoto T, Yamaguchi T, Shimada K, Korai M, Mure H, Okayama Y, Abe T, Harada M, Kitazato KT, Kanematsu Y
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: - Pages: 2134-2140
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats (2017)
  • Author(s): Maekawa Hidetsugu、Tada Yoshiteru、Yagi Kenji、Miyamoto Takeshi、Kitazato Keiko T.、Korai Masaaki、Satomi Junichiro、Hashimoto Tomoki、Nagahiro Shinji
  • Journal Title: J Neuroinflammation Volume: 14 Pages: 197-204
  • DOI: 10.1186/s12974-017-0966-7
  • Peer Reviewed / Open Access
• [Presentation] Pro-inflammatory response promoted by Porphyromonas gingivalis lipopolysaccharide enhances the rupture of experimental intracranial aneurysms. (2019)
  • Author(s): Yamaguchi T, Kitazato K, Shikata E, Yamagushi I, Miyamoto T, Korai M, Shimada K, Tada Y, Kanematsu Y, Takagi Y
  • Organizer: Brain and Brain PET2019
  • Int'l Joint Research
• [Presentation] 未破裂脳動脈瘤に対する薬物治療の可能性 (2018)
  • Author(s): 多田恵曜
  • Organizer: 第27回日本脳ドック学会総会
• [Presentation] Estrogen deficiency activates inflammasome in a rat model of intracranial aneurysms (2018)
  • Author(s): Yamaguchi Tadashi, Kitazato K, Miyamoto T, Korai M, Shimada K, Tada Y, Kanematsu Y, Satomi J, Nagahiro S, Takagi Y
  • Organizer: 11th World Stroke Congress 2018
  • Int'l Joint Research
• [Presentation] Pro-inflammatory Response Elicited by Porphyromonas Gingivalis Lipopolysaccharide Exacerbates the Rupture of Experimental Cerebral Aneurysms (2017)
  • Author(s): Miyamoto T, Kitazato K、Tada Y、Shimada K、Yagi K、 Korai、Maekawa H、Yamaguchi T、 Yoshioka S、 Kinouchi T、 Kanematsu Y、 Satomi J、Nagahiro S
  • Organizer: International Stroke Conference 2017
  • Int'l Joint Research
• [Presentation] Treatment strategy and outcom of ruptured vertebral artery dissecting aneurysms (2017)
  • Author(s): Korai M, Kanematsu Y, Tada Y, Yamaguchi I, Yamamoto N, Yamamoto Y, Satomi J
  • Organizer: 14TH CONGRESS OF THE WORLD FEDERATION OF INTERVENTIONAL AND THERAPEUTIC NEURORADIOLOGY
  • Int'l Joint Research