Molecular mechanisms underlying the rupture of cerebral aneurysms and the pharmacological regulation

• Project/Area Number: 24390344
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: NAGAHIRO Shinji 徳島大学, ヘルスバイオサイエンス研究部, 教授 (60145315)
• Co-Investigator(Kenkyū-buntansha): SATOMI Junichiro 徳島大学, 大学院ヘルスバイオサイエンス研究部, 准教授 (10304510) ; TADA Yoshiteru 徳島大学, 大学院ヘルスバイオサイエンス研究部, 助教 (30547964) ; KUWAYAMA Kauyuki 徳島大学, 病院, 講師 (50614236) ; MORIGAKI Ryoma 徳島大学, 大学院ヘルスバイオサイエンス研究部, 特任助教 (70710565) ; 兼松 康久 徳島大学, 大学病院, 助教 (90363142)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2012: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
• Keywords: 脳・神経 / 脳血管病 / エストロゲン / 脳動脈瘤破裂 / 血行動態変化 / 高血圧 / 結構動態変化 / 脳血管障害 / くも膜下出血 / 破裂脳動脈瘤 / 高塩食

Outline of Final Research Achievements

Subarachnoid hemorrhage is a catastrophic event and directs to high mobility and bad prognosis. To prevent this event, it is required to verify the pathogenesis. Hemodynamic stress is one of the initiating factors for cerebral aneurysmal formation. We hypothesized that additive hemodynamic change accelerates the development of aneurysms and studied the hypothesis. Ten-weeks-old Sprague-Dawley female rats were additively occluded in Rt.PPA and Rt.ECA. Their rupture incidence and the rupture rate were increased. The development of aneurysms at the circle of Willis may be partly attributable to hemodynamic change. Using this model we will study the efficacy of pharmacological treatment such as telmisartan, eplerenone or cilostazol. On the other hand, we started the clinical studies to assess the pharmacological treatment of cerebral aneurysms.

Research Products

• [Journal Article] Roles of Angiotensin (1-7) And Angiotensin II Type 2 Receptor on Intracranial Aneurysmal Rupture (2015)
  • Author(s): Shimada K, Wada K, Tada Y, A Kuwabara, Shikata F, Wei Y, Kitazato KT, Nagahiro S, Hashimoto T
  • Journal Title: Stroke Volume: 45
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice (2015)
  • Author(s): Shimada K, Furukawa H, Wada K, Wei Y, Tada Y, Kuwabara A, Shikata F, Kanematsu Y, Lawton MT, Kitazato KT, Nagahiro S, Hashimoto T
  • Journal Title: J Cereb Blood Flow Metab Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Roles of estrogen in the formation of intracranial aneurysms in ovariectomized female mice (2014)
  • Author(s): Tada Y, Makino H, Furukawa H, Shimada K, Wada K, Liang EI, Murakami S, Kudo M, Kung DK, Kitazato KT, Nagahiro S, Lawton MT, Hashimoto T
  • Journal Title: Neurosurgery Volume: 75 Pages: 690-695
  • Peer Reviewed / Open Access
• [Journal Article] Role of hypertension in the rupture of intracranial aneurysms (2014)
  • Author(s): Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Kitazato KT, Nagahiro S, Hashimoto T
  • Journal Title: Stroke Volume: 45 Pages: 579-586
  • Peer Reviewed / Open Access
• [Journal Article] Estrogen protects against intracranial aneurysm rupture in ovariectomized mice (2014)
  • Author(s): Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Shikata F, Silva RAP, Kitazato KT, Hasan DM, Kanematsu Y, Nagahiro S, Hashimoto T
  • Journal Title: Hypertension Volume: 63 Pages: 1339-1344
  • Peer Reviewed / Open Access
• [Journal Article] Estrogen protects against intracranial aneurysm rupture in ovariectomized mice (2014)
  • Author(s): Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Shikata F, Pena Silva RA, Kitazato KT, Hasan DM, Kanematsu Y, Nagahiro S, Hashimoto T
  • Journal Title: Hypertension Volume: in press
  • Peer Reviewed
• [Journal Article] 脳動脈瘤におけるNa+蓄積とRASの影響 (2013)
  • Author(s): 多田恵曜、北里慶子、永廣信治
  • Journal Title: Angiotensin Research Volume: 10 Pages: 84-92
• [Journal Article] Increase in body Na^<+->to^-water ratio is associated with cerebral aneurysm formation in oophorectomized rats (2012)
  • Author(s): Nobuhisa Matsushita, et al.
  • Journal Title: Hypertension Volume: 60 Pages: 1309-1315
  • Peer Reviewed
• [Presentation] Role of hyperhomocysteinemia in the development of intracranial aneurysms (2015)
  • Author(s): Korai M, Kitazato KT, Miyamoto T, Shimada K, Yagi K, Tada Y, Kurashiki Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: International Stroke Conference
  • Place of Presentation: Nashville、USA
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Hemodynamic change elicits the formation and rupture of experimental cerebral aneurysms (2015)
  • Author(s): Miyamoto T,, David K. Kung, Korai M, Kitazato KT, Shimada K, Yagi K, Tada Y, Kurashiki Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: International Stroke Conference
  • Place of Presentation: Nashville、USA
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Is the regulation of M1 macrophage activation beneficial in the acute phase of post cerebral ischemia? (2015)
  • Author(s): Kurashiki Y, Kitazato K, Uto Y, Yagi K, Shimada K, Miyamoto T, Sumiyoshi M, Tada Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: International Stroke Conference
  • Place of Presentation: Nashville、USA
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Protective effects of estrogen receptor-beta against the formation of intracranial aneurysms in mice (2014)
  • Author(s): Tada Y, Makino H., Wada K., Shimada K., Liang E., Murakami S., Kudo M, Kitazato KT., Nagahiro S., Hashimoto T
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Activation of M2 macrophage in the late phase after cerebral ischemia promotes the expression of neurogenesis related molecules (2014)
  • Author(s): Kurashiki Y, Kitazato K1, Uto Y, Yagi K, Shimada K, Miyamoto T1, Sumiyoshi M, Tada Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Is the regulation of M1 macrophage activation beneficial in the acute phase of post cerebral ischemia? (2014)
  • Author(s): Kurashiki Y, Kitazato K1, Uto Y, Yagi K, Shimada K, Miyamoto T1, Sumiyoshi M, Tada Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Hemodynamic changes may elicit the formation and rupture of experimental cerebral aneurysms (2014)
  • Author(s): Miyamoto T, David K. Kung, Korai M, Kitazato KT, Shimada K, Yagi K, Tada Y, Kurashiki Y, Kuwayama K, Satomi J, Nagahiro S
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Role of angiotensin (1-7) and angiotensin type 2 receptor on intracranial aneurysmal rupture (2014)
  • Author(s): Shimada K, K.Wada, H.Furukawa, Y.Wei, Y.Tada, A.Kuwabara, F.Shikata, K.T.Kitazato, S.Nagahiro, T.Hashimoto
  • Organizer: 9th World Stroke Congress
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] Role of angiotensin (1-7) and angiotensin type 2 receptor on intracranial aneurysmal rupture (2014)
  • Author(s): Shimada K, Wada K, Tada Y, Wei Y, Kuwabara A, Shikata F, Furukawa H, Kitazato KT, Nagahiro S, Hashimoto T
  • Organizer: International Stroke Conference 2014
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
• [Presentation] Role of hyperhomocysteinemia in the development of intracranial aneurysms (2013)
  • Author(s): Korai M, Kung DK, Kitazato KT, Matsushita N, Tada Y, Yagi K, Shimada K, Kanematsu Y, Satomi J, Nagahiro S
  • Organizer: Congress of Neurological Surgeons 2013
  • Place of Presentation: Moscone West Convention Center (San Francisco, USA)
• [Presentation] Estrogen protects against aneurysmal rupture through estrogen receptor-beta in ovariectomized mice (2013)
  • Author(s): Yoshiteru Tada, et al.
  • Organizer: International Stroke Conference 2013
  • Place of Presentation: ヒルトンハワイアンビレッジ(アメリカ合衆国)
• [Presentation] Imbalance between activation of matrix metalloprotease and its inhibition may facilitate (2013)
  • Author(s): Masaaki Kohrai, et al.
  • Organizer: International Stroke Conference 2013
  • Place of Presentation: ヒルトンハワイアンビレッジ(アメリカ合衆国)
• [Presentation] 卵巣摘出マウスにおいて、エストロゲンはエストロゲン受容体-betaを介して脳動脈瘤破裂を抑制する (2013)
  • Author(s): 多田恵曜, 他
  • Organizer: 第38回日本脳卒中学会総会
  • Place of Presentation: グランドプリンスホテル新高輪(東京都)
• [Presentation] The significance of endovascular therapy in vertebral artery dissecting aneurysm (2012)
  • Author(s): Masaaki Kohrai, et al.
  • Organizer: 10th Meeting of Asian Australasian Federation of Interventional and Therapeutic Neuroradiology
  • Place of Presentation: 名古屋国際会議場(愛知県)