Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats

Hidetsugu Maekawa, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. hidetsugumaekawa@yahoo.co.jp.
Yoshiteru Tada, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Kenji Yagi, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Takeshi Miyamoto, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Keiko T. Kitazato, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Masaaki Korai, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Junichiro Satomi, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Tomoki Hashimoto, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, SFGH 1, San Francisco, CA, 94110, USA.Follow
Shinji Nagahiro, Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.

Document Type

Article

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.

Keywords

Estrogen, Estrogen receptor, Intracranial aneurysm, Selective estrogen receptor modulator, Subarachnoid hemorrhage

Medical Subject Headings

Animals; Blood Pressure (drug effects); Cerebral Arteries (drug effects, metabolism); Cytokines (genetics); Disease Models, Animal; Dose-Response Relationship, Drug; Estrogen Receptor alpha (genetics, metabolism); Estrogen Receptor beta (genetics, metabolism); Female; Gene Expression Regulation (drug effects, genetics); Hypertension (chemically induced, complications); Indoles (therapeutic use); Intracranial Aneurysm (drug therapy, etiology); Matrix Metalloproteinase 2 (metabolism); Ovariectomy; RNA, Messenger (metabolism); Rats; Rats, Sprague-Dawley; Salts (toxicity); Selective Estrogen Receptor Modulators (therapeutic use); Tissue Inhibitor of Metalloproteinase-2 (genetics, metabolism)

Publication Date

10-2-2017

Publication Title

Journal of neuroinflammation

E-ISSN

1742-2094

Volume

14

Issue

1

First Page

197

PubMed ID

28969701

Digital Object Identifier (DOI)

10.1186/s12974-017-0966-7

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