Role of selective estrogen receptor modulators on cerebrovascular diseases

• Project/Area Number: 26462159
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: 独立行政法人国立病院機構四国こどもとおとなの医療センター(臨床研究部(成育)、臨床研究部(循環器)) (2015-2016); The University of Tokushima (2014)
• Principal Investigator: Kuwayama Kazuyuki 独立行政法人国立病院機構四国こどもとおとなの医療センター(臨床研究部(成育)、臨, 臨床研究部, 脳神経外科医長 (50614236)
• Co-Investigator(Kenkyū-buntansha): 里見 淳一郎 徳島大学, 大学院医歯薬学研究部(医学系), 准教授 (10304510) ; 多田 恵曜 徳島大学, 大学院医歯薬学研究部(医学系), 講師 (30547964) ; 永廣 信治 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (60145315)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脳血管病 / エストロゲン受容体α/β / エストロゲン受容体調節薬 / 脳動脈瘤破裂 / エストロゲン受容体作動薬(SERM） / エストロゲン受容体作動薬（SERM）

Outline of Final Research Achievements

Severe ischemic stroke and subarachnoid hemorrhage due to rupture of cerebral aneurysms are catastrophic and poor prognosis. Hormonal replacement therapy does not necessarily result in the good outcome. Elsewhere we demonstrated the beneficial role of estrogen receptors (ERs) against brain vascular diseases. In this study, we focused on the role of ERs. Since the affinity of estrogen to ERα is 1000 times higher than ERβ, ERα acts mainly under its presence. ERβ is thought to compensate when ERα is downregulated. We treated with a selective ER modulator (SERM) approved for osteoporosis in the cerebral aneurysm model rats. SERM was protective against cerebral aneurysm rupture; the inhibition of a cytokine, IL-1β and a vascular degradation molecule, MMP-9 by SERM was attributable to the efficacy. We are planning to identify the risk factors associated with the expression of cytokine and vascular degradation molecules and to clarify the role of SERM against cerebral ischemia.

Research Products

• [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] 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] 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] Improvement of plasma biomarkers including angiotensin-(1-7) after switching from other angiotensin II type I receptor blockers to olmesartan in stroke patients with insufficient blood pressure control (2015)
  • Author(s): Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi, J, Kitazato, K, Kageji T, Matsuura E, Nagahiro S
  • Journal Title: J stroke cerebrovasc dis Volume: in press
  • Peer Reviewed
• [Journal Article] Intra-arterial signal on arterial spin labeling perfusion MRI to identify the presence of acute middle cerebral artery occlusion (2014)
  • Author(s): Tada Y, Satomi J, Abe T, Kuwayama K, Sogabe S, Fujita K, Yamamoto N, Kaji R, Harada M, Nagahiro S
  • Journal Title: Cerebrovasc Dis Volume: 38 Pages: 191-196
  • Peer Reviewed
• [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: 63 Pages: 1339-1344
  • Peer Reviewed
• [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, S. Nagahiro
  • 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
  • Int'l Joint Research
• [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
  • Int'l Joint Research