Role of selective estrogen receptor modulator on the formation and rupture of intracranial aneurysms

• Project/Area Number: 15K19972
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: TADA Yoshiteru 徳島大学, 大学院医歯薬学研究部(医学系), 講師 (30547964)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脳・神経 / 脳神経疾患 / 選択的エストロゲン受容体作動薬 / 脳動脈瘤破裂 / くも膜下出血

Outline of Final Research Achievements

Estrogen and estrogen receptor agonist prevented the formation and rupture of intracranial aneurysms in animal models. However, estrogen replacement therapy is associated with side effects such as endometrial- and breast cancer. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor modulator with fewer estrogenic side effects, prevented aneurysmal rupture in our aneurysm model rats. Intracranial aneurysms were induced by hemodynamic stress, hypertension, and estrogen deficiency in female rats. Bazedoxifene prevented aneurysmal rupture without affecting the blood pressure. The protective effects against the aneurysmal rupture of bazedoxifene was associated with the increased expression of estrogen receptors and the decreased in the ratio of the matrix metalloproteinase-9 to the tissue inhibitor of metalloproteinase-2 expression.

Research Products

• [Int'l Joint Research] University of California, San Francisco(米国)
• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] Toronto University(カナダ)
• [Journal Article] Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment (2017)
  • Author(s): Sogabe S, Satomi J, Tada Y, Kanematsu Y, Kuwayama K, Yagi K, Yoshioka S, Mizobuchi Y, Mure H, Yamaguchi I, Abe T, Yamamoto N, Kitazato KT, Kaji R, Harada M, Nagahiro S
  • Journal Title: Neuroradiology. Volume: － Issue: 6 Pages: 587-595
  • DOI: 10.1007/s00234-017-1828-9
  • Peer Reviewed / Open Access
• [Journal Article] Treatment Outcome of Carotid Artery Stenting Underwent within 14 Days of Stroke Onset – Consideration of Safety and Efficacy of Urgent Carotid Artery Stenting for Neurologically Progressing Patients (2017)
  • Author(s): Kanematsu Y, Satomi J, Kuwayama K, Yamaguchi I, Yoshioka S, Kinouchi T, Tada Y, Yamamoto N, Matsubara S, Satoh K, Nagahiro S
  • Journal Title: Neurologia medico-chirurgica Volume: 57 Issue: 6 Pages: 278-283
  • DOI: 10.2176/nmc.oa.2016-0236
  • NAID: 130006882460
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats, J Neuroinflammation (2016)
  • Author(s): Korai M, Kitazato KT, Tada Y, Miyamoto T, Shimada K, Matsushita N, Kanematsu Y, Satomi J, Hashimoto T, Nagahiro S
  • Journal Title: J Neuroinflammation Volume: 13 Issue: 1 Pages: 165-175
  • DOI: 10.1186/s12974-016-0634-3
  • Peer Reviewed / Open Access
• [Journal Article] Site-specific elevation of interleukin-1β and matrix metalloproteinase-9 in the Willis circle by hemodynamic changes is associated with rupture in a novel rat cerebral aneurysm model (2016)
  • Author(s): Miyamoto T, Kung DK, Kitazato KT, Yagi K, Shimada K, Tada Y, Korai M, Kurashiki Y, Kinouchi T, Kanematsu Y, Satomi J, Hashimoto T, Nagahiro S
  • Journal Title: J Cereb Blood Flow Metab Volume: － Issue: 8 Pages: 2795-2805
  • DOI: 10.1177/0271678x16675369
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 M, Kitazato K, Nagahiro S, Hashimoto T
  • Journal Title: J Cereb Blood Flow Metab Volume: 35 Issue: 7 Pages: 1163-1168
  • DOI: 10.1038/jcbfm.2015.30
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan (2015)
  • Author(s): Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi J, Kitazato KT, Kageji T, Matsuura E, Nagahiro S
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Issue: 7 Pages: 1487-1492
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.015
  • Peer Reviewed / Open Access
• [Journal Article] Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture (2015)
  • Author(s): Shimada K, Furukawa H, Wada K, Korai M, Wei Y, Tada Y, Kuwabara A, Shikata F, Kitazato KT, Nagahiro S, Lawton MT, Hashimoto T
  • Journal Title: Stroke Volume: 46 Issue: 6 Pages: 1664-1672
  • DOI: 10.1161/strokeaha.114.007722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Porphyromonas gingivalis lipopolysaccharide enhances the rupture of intracranial aneurysms in rats (2016)
  • Author(s): Miyamoto T, Kitazato K, Maekawa H,Yamaguchi T, Shimada K, Yagi K, Tada Y, Kurashiki Y, Yoshioka S, Kanematsu Y, Satomi J, Nagahiro S
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Venice, Italy
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Activation of M2 macrophages in the late phase of cerebral ischemia may contribute to phagocytosis of infarct area and neurogenesis (2016)
  • Author(s): Kurashiki Y, Kitazato K, Shimada K, Yagi K, Tada Y, Kinouchi T, Sumiyoshi M, Miyamoto T, Yamaguchi T, Satomi J, Uto Y, Nagahiro S
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Venice, Italy
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Impact of Periodontal Disease and －Bacteria on Intracranial Aneurysms (2016)
  • Author(s): S. Yoshioka, Y. Tada, J. Satomi, K. Yagi, K. Naruishi, K. Kuwayama, K. T. Kitazato, T. Miyamoto, Y. Kanematsu, M. Harada, T. Nagata, Nagahiro S.
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Early Morphological Changes in Cerebral Arteries of Cerebral Aneurysm Rupture Model Rats (2016)
  • Author(s): H. Maekawa, T. Miyamoto, K.T. Kitazato, K. Yagi, Y. Tada, K. Shimada, J. Satomi, S Nagahiro.
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
• [Presentation] A Pilot Study of the Mineralocorticoid Receptor Blocker Eplerenone in Hypertensive Patients with Unruptured Cerebral Aneurysms (2016)
  • Author(s): J. Satomi, Y. Tada, Y. Kanematsu, K. Kuwayama, K. Yagi, T. Kinouchi, K. Nakajima, N. Matsushita, T. Miyamoto, T. Yamaguchi, M. Korai, H. Mure, K. T. Kitazato, S Nagahiro.
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17