脳動脈瘤研究

徳島大学医歯薬学研究部脳神経外科研究室

脳血管障害研究（脳動脈瘤、脳梗塞、脳動静脈奇形）

脳動脈瘤研究

脳動脈瘤は閉経期の女性に発生する頻度が高いことから、卵巣摘出によるエストロゲン欠乏、高血圧誘導（OVX+/HT）および血行動態変化を誘導した独自の脳動脈瘤ラットモデルを世界的に初めて確立し、世界脳神経外科学会で受賞し、韓国KBS放送から取材を受け、1時間の特集番組で報道されています. また、英文誌やモデル動物の書籍にも掲載されています。さらに、ホルモン補充療法によりエストロゲン欠乏が脳動脈瘤発生・増大には関与することを実証し、血行動態変化による内皮障害の関与や血管壁の炎症性変化の関与も明らかにしています。

Corrosion cast による電子顕微鏡察

近年、学内歯学部との共同臨床研究において、破裂しやすい脳動脈瘤と歯周病の重症度との関連性を明らかにし、歯周病の重症化予防が動脈瘤の増大-破裂抑制に必要であることを立証しています。

また、増大-破裂予防に有効な薬物療法を検討し、抗炎症作用のあるイブジラストや降圧剤のアンジオテンシンII受容体拮抗薬（ARB）および選択的ミネラロコルチコイド受容体拮抗薬(エプレレノン)の脳動脈瘤形成、増大抑制効果をモデル動物で示しています。これらの知見をもとに、脳動脈瘤に対する薬物治療の有効性を徳島大学関連病院との共同研究で初めて検討し、エプレレノンによる有効性を報告しています。世界に先駆けた、他に例を見ない研究成果を上げており、増大・破裂予知に繋がる研究や破裂予後の改善に向けた検討を推進しています。

特許取得

Yagi K, Kitazato KT, Nagahiro S. イブジラストによる脳動脈瘤増大抑制効果

発表論文

  1. Shikata E, Tamura T, Shinno K, Okayama Y, Shinohara N, Shimada K, Kanematsu Y, Kitazato KT, Nagahiro S, Takagi Y.　Importance of Managing the Water-Electrolyte Balance by Delivering the Optimal Minimum Amount of Water and Sodium After Subarachnoid Hemorrhage.World Neurosurg. 2019 Sep;129:e352-e360
  2. Yamaguchi T, Miyamoto T, Kitazato KT, Shikata E, Yamaguchi I, Korai M, Shimada K, Yagi K, Tada Y, Matsuzaki Y, Kanematsu Y, Takagi Y.J Neurosurg. Time-dependent and site-dependent morphological changes in rupture-prone arteries: ovariectomized rat intracranialaneurysmJ Neurosurg. 2019 Sep 13:1-9. 
  3. Kanematsu Y, Satomi J, Korai M, Okazaki T, Yamaguchi I, Tada Y, Uno M, Nagahiro S, Takagi Y.　Flow Alteration Therapy for Ruptured Vertebral Artery Dissecting Aneurysms Involving the Posterior Inferior Cerebellar Artery. Neurol Med Chir (Tokyo). 2018 Aug 15;58(8):341-349.
  4. 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.Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study.J Stroke Cerebrovasc Dis. 2018 Aug;27(8):2134-2140.
  5. Maekawa H, Tada Y, Yagi K, Miyamoto T, Kitazato KT, Korai M, Satomi J, Hashimoto T, Nagahiro S. Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysmrupture in Ovariectomized rats. Neuroinflammation. 2017 Oct 2;14(1):197
  6. 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 Site-specific elevation of interleukin-1beta and matrix metalloproteinase-9 in the Willis circle by hemodynamic changes is associated with rupture in a novel rat cerebral aneurysm .J Cereb Blood Flow Metab. 2017 Aug;37(8):2795-2805. 
  7. Korai M, Kitazato KT, Tada Y, Miyamoto T, Shimada K, Matsushita N, Kanematsu Y, Satomi J, Hashimoto T, Nagahiro S. Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats. J Neuroinflammation. 2016 Jun 27;13(1):165. 
  8. Shimada K, Furukawa H, Wada K, Wei Y, Tada Y, Kuwabara A, Shikata F, Kanematsu Y, Lawton MT, Kitazato KT, Nagahiro S, Hashimoto T. Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice.　J Cereb Blood Flow Metab. 2015 Jul;35(7):1163-
  9. Shimada K, Furukawa H, Wada K, Korai M, Wei Y, Tada Y, Kuwabara A, Shikata F, Kitazato KT, Nagahiro S, Lawton MT, Hashimoto T. Protective Role of Peroxisome Proliferator-Activated Receptor-gamma in the Development of IntracranialAneurysm Stroke. 2015 Jun;46(6):1664-72.
  10. 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.　Estrogen protects　against intracranialaneurysm rupture in ovariectomized mice. 2014 Jun;63(6):1339-44.
  11. Tada Y, Makino H, Furukawa H, Shimada K, Wada K, Liang EI, Murakami S, Kudo M, Kung DK, Hasan DM, Kitazato KT, Nagahiro S, Lawton MT, Hashimoto Roles of estrogen in the formation of intracranialaneurysms in ovariectomized female mice.Neurosurgery. 2014 Dec;75(6):690-5
  12. Tada Y, Wada K, Shimada K, Makino H, Liang EI, Murakami S, Kudo M, Kitazato KT, Nagahiro S, Hashimoto T. Roles of hypertension in the rupture of intracranialaneurysms.　 2014 Feb;45(2):579-86. 
  13. Matsushita N, Kitazato KT, Tada Y, Sumiyoshi M, Shimada K, Yagi K, Kanematsu Y, Satomi J, Nagahiro S.　Increase in body Na+/water ratio is associated with cerebral aneurysmformation in oophorectomized rats. 2012 Nov;60(5):1309-15.
  14. Kruppel-like zinc-finger transcription factor 5 (KLF5) is highly expressed in large and giant unruptured cerebral aneurysms.Nakajima N, Nagahiro S, Sano T, Satomi J, Tada Y, Yagi K, Kitazato KT, Satoh K.World Neurosurg. 2012 ;78(1-2):114-21
  15. Tada Y, Kitazato KT, Yagi K, Shimada K, Matsushita N, Kinouchi T, Kanematsu Y, Satomi J, Kageji T, Nagahiro S. Statins promote the growth of experimentally induced cerebral aneurysmsin estrogen-deficient rats. 2011 42(8):2286-93
  16. Tada Y, Yagi K, Kitazato KT, Tamura T, Kinouchi T, Shimada K, Matsushita N, Nakajima N, Satomi J, Kageji T, Nagahiro S. Reduction of endothelial tight junction proteins is related to cerebral aneurysmformation in rats.J Hypertens. 2010 Sep;28(9):1883-91.
  17. Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S. Ibudilast inhibits cerebral aneurysmsby down-regulating inflammation-related molecules in the vascular wall of rats. 2010 Mar;66(3):551-9
  18. Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, Satomi J, Nagahiro S Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats. 2009 Sep;54(3):552-7
  19. Tamura T, Jamous MA, Kitazato KT, Yagi K, Tada Y, Uno M, Nagahiro S Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysmformation in female rats.J Hypertens. 2009;27(6):1284-92.
  20. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Aziz HA, Shono M, Satoh K Endothelial injury and inflammatory response induced by hemodynamic preceding changes intracranial aneurysmformation: experimental study in rats..J Neurosurg. 2007 Aug;107(2):405-11. 
  21. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Kuwayama K, Satoh K. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J Neurosurg. 2005 Dec;103(6):1052-7.
  22. Jamous MA, Nagahiro S, Kitazato KT, Satomi J, Satoh K. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part I: experimental study of the effect of oophorectomy in rats. J Neurosurg. 2005 Dec;103(6):1046-51
  23. Jamous MA, Nagahiro S, Kitazato KT, Satoh K, Satomi J. Vascular corrosion casts mirroring early morphological changes that lead to the formation of saccular cerebral aneurysm: an experimental study in rats. J Neurosurg. 2005 Mar;102(3):532-5.
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