Early diagnosis and pharmacological treatment to prevent the rupture of cerebral aneurysms

• Project/Area Number: 15H04950
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: NAGAHIRO Shinji 徳島大学, 病院, 病院長 (60145315)
• Co-Investigator(Kenkyū-buntansha): 多田 恵曜 徳島大学, 大学病院, 特任講師 (30547964) ; 兼松 康久 徳島大学, 病院, 特任准教授 (90363142) ; 桑山 一行 徳島大学, 大学病院, 非常勤講師 (50614236) ; 八木 謙次 徳島大学, 大学病院, 講師 (80551837)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 脳・神経 / 脳血管病 / エストロゲン受容体調整薬 / 脳動脈瘤破裂 / エストロゲン / 血行動態変化 / 高血圧 / 脳動脈瘤 / 歯周病 / 脳動脈瘤破裂 血行動態変化

Outline of Final Research Achievements

Subarachnoid hemorrhage due to rupture of cerebral aneurysms are catastrophic and poor prognosis. Therefore, new therapeutic strategies are required to prevent the events. Estrogen deficiency is at least partly attributable to the pathogenesis, while hormonal replacement therapy does not necessarily result in the good outcome. Elsewhere we demonstrated the beneficial role of estrogen receptors (ER) against brain vascular diseases in our aneurysm models. We also demonstrated the efficacy of anti-hypertensive drugs and a selective ER modulator (SERM) approved for osteoporosis, in the cerebral aneurysm model rats and identified the risk factors associated with the expression of cytokine and vascular degradation molecules. In our pilot study, we first demonstrated that an anti-hypertensive drug, eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9mm. We need further clinical studies in larger scale.

Research Products

• [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: J Stroke Cerebrovasc Dis Volume: -
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of Clinical Characteristics among Subtypes of Visual Symptoms in Patients with Transient Ischemic Attack: Analysis of the PROspective Multicenter registry to Identify Subsequent cardiovascular Events after TIA (PROMISE-TIA) Registry (2018)
  • Author(s): Tanaka Koji、Uehara Toshiyuki、Kimura Kazumi、Okada Yasushi、Hasegawa Yasuhiro、Tanahashi Norio、Suzuki Akifumi、Nakagawara Jyoji、Arii Kazumasa、Nagahiro Shinji、Ogasawara Kuniaki、Uchiyama Shinichiro、Matsumoto Masayasu、Iihara Koji、Toyoda Kazunori、Minematsu Kazuo
  • Journal Title: J Stroke Cerebrovasc Dis Volume: -
  • DOI: 10.1016/j.jstrokecerebrovasdis.2018.01.031
  • Peer Reviewed / Open Access
• [Journal Article] Coloring Technique of Magnetic Resonance Angiography for Superficial Temporal Artery to Middle Cerebral Artery Bypass Surgery (2018)
  • Author(s): Okazaki Toshiyuki、Irie Shinsuke、Inagaki Toru、Saito Osamu、Yamashina Motoshige、Hayase Hitoshi、Nakagawa Hiroshi、Nagahiro Shinji、Saito Koji
  • Journal Title: 10.1016/j.wneu.2017.12.152 Volume: -
  • DOI: 10.1016/j.wneu.2017.12.152
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats (2017)
  • Author(s): Kinouchi Tomoya、Kitazato Keiko T.、Shimada Kenji、Yagi Kenji、Tada Yoshiteru、Matsushita Nobuhisa、Kurashiki Yoshitaka、Satomi Junichiro、Sata Masataka、Nagahiro Shinji
  • Journal Title: Translational Stroke Research Volume: -
  • DOI: 10.1007/s12975-017-0577-8
  • 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
• [Journal Article] Pulsatile Tinnitus due to an Aberrant Internal Carotid Artery in the Middle Ear:A Case Report (2017)
  • Author(s): Kuwayama K, Satomi J, Yamaguchi T, Yamaguchi I, Sogabe S, Yoshioka S, Nagahiro S
  • Journal Title: Neurological Surgery Volume: 45 Pages: 321-324
  • Peer Reviewed / Open Access
• [Journal Article] ntra-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: － 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: Neurol. Med. Chir.(Tokyo) Volume: － Issue: 6 Pages: 278-283
  • DOI: 10.2176/nmc.oa.2016-0236
  • NAID: 130006882460
  • 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: －
  • DOI: 10.1177/0271678x16675369
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The unruptured intracranial aneurysm treatment score (2015)
  • Author(s): Etminan N, Brown RD Jr, Beseoglu K, Juvela S, Raymond J, Morita A, Torner JC, Derdeyn CP, Raabe A, Mocco J, Korja M, Abdulazim A, Amin-Hanjani S, Al-Shahi Salman R, Barrow DL, Bederson J, Bonafe A, Dumont AS, Fiorella DJ, Gruber A, Hankey GJ, Hasan DM, Hoh BL, Jabbour P
  • Journal Title: Neurology Volume: 85 Pages: 881-889
  • DOI: 10.1212/wnl.0000000000001891
  • Open Access / Int'l Joint Research
• [Journal Article] DIAS-J Investigators Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke (2015)
  • Author(s): Mori E, Minematsu K, Nakagawara J, Hasegawa Y, Nagahiro S, Okada Y, Truelsen T, Lindsten A, Ogawa A, Yamaguchi T
  • Journal Title: Stroke Volume: 46 Pages: 2549-2554
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage (2015)
  • Author(s): Yagi K, Lidington D, Wan H, Fares JC, Meissner A, Sumiyoshi M, Ai J1, Foltz WD, Nedospasov SA, Offermanns S, Nagahiro S, Macdonald RL, Bolz SS
  • Journal Title: Stroke Volume: 46 Pages: 2260-2270
  • DOI: 10.1161/strokeaha.114.006365
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intraoperative Arachnoid Plasty Has Possibility to Prevent Chronic Subdural Hematoma after Surgery for Unruptured Cerebral Aneurysms (2015)
  • Author(s): Yagi K, Irie S, Inagaki T, Ishii Y, Saito O, Lee T, Nakagawa H, Saito K, Nagahiro S
  • Journal Title: Neurol. Med. Chir.(Tokyo) Volume: 55 Issue: 6 Pages: 493-497
  • DOI: 10.2176/nmc.oa.2014-0455
  • NAID: 130005076045
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The accumulation of brain water-free sodium is associated with ischemic damage independent of the blood pressure in female rats (2015)
  • Author(s): Sumiyoshi M, Kitazato KT, Yagi K, Miyamoto T, Kurashiki Y, Matsushita N, Kinouchi T, Kuwayama K, Satomi J, Nagahiro S
  • Journal Title: Brain Res Volume: 1616 Pages: 37-44
  • DOI: 10.1016/j.brainres.2015.04.051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: 1664-1672
  • DOI: 10.1161/strokeaha.114.007722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PPARγ-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates Ischemic Brain Damage in Ovariectomized Rats (2015)
  • Author(s): Sumiyoshi M, Satomi J, Kitazato KT, Yagi K, Shimada K, Kurashiki Y, Korai M, Miyamoto T, Suzue R, Kuwayama K, Nagahiro S
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Pages: 1187-1195
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.01.009
  • Peer Reviewed / Open Access
• [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 Pages: 1487-1492
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.015
  • 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 M, Kitazato K, Nagahiro S, Hashimoto T
  • Journal Title: J Cereb Blood Flow Metab Volume: 35 Pages: 1163-1168
  • DOI: 10.1038/jcbfm.2015.30
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prevention of Retrograde Blood Flow Into Large or Giant Internal Carotid Artery Aneurysms by Endovascular Coil Embolization with High-Flow Bypass (2015)
  • Author(s): Nakajima N, Nagahiro S, Satomi J, Tada Y, Nakajima K, Sogabe S, Hanaoka M, Matsubara S, Uno M, Satoh K
  • Journal Title: World Neurosurg Volume: 83 Pages: 1127-1134
  • DOI: 10.1016/j.wneu.2015.01.037
  • Peer Reviewed / Open Access
• [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] Roles of Neutrophil Extracellular Trap in the Rupture of Intracranial Aneurysm (2017)
  • Author(s): Korai M, Furukawa H、Kamio Y、Mitsui K、Nagahiro S、Hashimoto T
  • Organizer: International Stroke Conference 2017
  • Int'l Joint Research
• [Presentation] Activation of M2 macrophages in the late phase of cerebral ischema may contribute to phagocytosis of infract area and neurogenesis (2016)
  • Author(s): Y. Kurashiki, K.T. Kitazato, K. Shimada, K. Yagi, Y. Tada, T. Kinouchi, M. Sumiyoshi, T. Miyamoto, T. Yamaguchi, J. Satomi, Y. Uto, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Italy(Venice)
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] Porphyromonas gingivalis lipopolysaccharide enhances the rupture of intracranial aneurysms in rats (2016)
  • Author(s): T. Miyamoto, K.T. Kitazato, H. Maekawa, T. Yamaguchi, K. Shimada, K. Yagi, Y. Tada, Y. Kurashiki, S. Yoshioka, Y. Kanematsu, J. Satomi, S. Nagahiro
  • Organizer: 25th European Stroke Conference
  • Place of Presentation: Italy(Venice)
  • Year and Date: 2016-04-13
  • 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] 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] 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
• [Presentation] 3D structure of vasa vasorum in thrombosed rat cerebral aneurysms (2016)
  • Author(s): H. Maekawa, T. Miyamoto, K.T. Kitazato, S. Nagahiro
  • Organizer: ABC－WIN Seminar
  • Place of Presentation: Paris, France
  • Year and Date: 2016-01-17
  • Int'l Joint Research