徳島大学 教育・研究者情報データベース(EDB)

1. (英) Maekawa Hidetsugu / (日) 前川 秀継 / (読) まえかわ ひでつぐ

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2. 多田 恵曜([徳島大学.病院.中央診療施設等.てんかんセンター])

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3. 八木 謙次

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4. 宮本 健志([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.外科系.脳神経外科学]/[徳島大学.病院.診療科.脳·神経·精神科.脳神経外科])

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5. (英) Keiko T. Kitazato

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6. 高麗 雅章

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7. 里見 淳一郎

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8. (英) Hashimoto Tomoki

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9. 永廣 信治

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(英) Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats.

(英) Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed. During 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERβ, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1β and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERβ and decreased the level of interleukin-1β and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERβ. Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.

1. (英) Animals
2. 血圧(blood pressure)
3. (英) Cerebral Arteries
4. (英) Cytokines
5. (英) Disease Models, Animal
6. (英) Dose-Response Relationship, Drug
7. (英) Estrogen Receptor alpha
8. (英) Estrogen Receptor beta
9. (英) Female
10. (英) Gene Expression Regulation
11. 高血圧(hypertension)
12. (英) Indoles
13. (英) Intracranial Aneurysm
14. (英) Matrix Metalloproteinase 2
15. (英) Ovariectomy
16. (英) RNA, Messenger
17. (英) Rats
18. (英) Rats, Sprague-Dawley
19. (英) Salts
20. (英) Selective Estrogen Receptor Modulators
21. (英) Tissue Inhibitor of Metalloproteinase-2

1. (英) Article.ELocationID: 10.1186/s12974-017-0966-7

2. (英) Article.PublicationTypeList.PublicationType: Journal Article

3. (英) KeywordList.Keyword: Estrogen

4. (英) KeywordList.Keyword: Estrogen receptor

5. (英) KeywordList.Keyword: Intracranial aneurysm

6. (英) KeywordList.Keyword: Selective estrogen receptor modulator

7. (英) KeywordList.Keyword: Subarachnoid hemorrhage