Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, SFGH 1, San Francisco, CA, 94110, USA.
J Neuroinflammation. 2017 Oct 2;14(1):197. doi: 10.1186/s12974-017-0966-7.
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.
雌激素缺乏被认为是绝经后女性比绝经前女性更易发生蛛网膜下腔出血的原因。雌激素替代疗法似乎可以降低这种风险，但也存在显著的副作用。我们通过新的卵巢切除大鼠模型验证了我们的假设，即具有较少雌激素副作用的临床应用的选择性雌激素受体（ER）调节剂巴多昔芬可减少脑动脉瘤破裂。
将 10 周龄雌性 Sprague-Dawley 大鼠进行卵巢切除术、血流动力学变化和高血压处理，以诱导动脉瘤（卵巢切除动脉瘤大鼠），并用载体或 0.3 或 1.0mg/kg/天巴多昔芬治疗。将它们与接受高血压和血流动力学变化的假卵巢切除大鼠（HT 大鼠）进行比较。分析了巴多昔芬的血管保护作用及其疗效的机制。
在 12 周的观察期间，卵巢切除大鼠的动脉瘤破裂发生率为 52%。用 0.3 或 1.0mg/kg/天巴多昔芬治疗，对血压无影响，可将这一比率降低至 11%和 17%，与 HT 大鼠（17%）几乎相同。在卵巢切除大鼠中，在动脉瘤诱导后 5 周，易破裂的大脑动脉中 ERα、ERβ 和基质金属蛋白酶-2 组织抑制剂的 mRNA 水平下调；白细胞介素-1β 和基质金属蛋白酶-9 的 mRNA 水平上调。在 HT 大鼠中，巴多昔芬恢复了 ERα 和 ERβ 的 mRNA 水平，并降低了白细胞介素-1β 和基质金属蛋白酶-9 的水平。这些发现表明，巴多昔芬通过减轻 ERα 和 ERβ 减少引起的血管炎症和降解来保护动脉瘤破裂。
我们观察到巴多昔芬降低了卵巢切除大鼠的动脉瘤破裂发生率，这需要进一步的研究来验证人类对此的反应。
