Glucocorticoid Insensitivity at the Hypoxic Blood-Brain Barrier Can Be Reversed by Inhibition of the Proteasome
Glucocorticoid Insensitivity at the Hypoxic Blood-Brain Barrier Can Be Reversed by Inhibition of the Proteasome
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DOI：
10.1161/strokeaha.110.592238
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发表时间：
2011-04-01
期刊：
影响因子：
8.3
通讯作者：
Foerster, Carola
中科院分区：
文献类型：
--
作者：
Kleinschnitz, Christoph;Blecharz, Kinga;Foerster, Carola
背景和目的-糖皮质激素在某些中枢神经系统肿瘤和炎症性疾病中有效地稳定血脑屏障和改善组织水肿，但在急性缺血性中风患者中大多无效。这种差异的原因尚未解决。方法-为了解决低氧时血脑屏障反常无反应的分子基础，我们使用暴露于O-2/葡萄糖剥夺的小鼠脑微血管内皮细胞作为体外模型。在活体方法中，小鼠受到一过性大脑中动脉闭塞以诱导脑梗塞。在蛋白酶体抑制剂存在或不存在的情况下，选择血脑屏障损伤和水肿形成作为糖皮质激素敏感性的替代指标。结果-O-2/葡萄糖剥夺可降低体外培养的小鼠脑微血管内皮细胞紧密连接蛋白的表达和跨内皮细胞阻力。地塞米松治疗在低氧时未能逆转这些效应。蛋白酶体依赖的糖皮质激素受体的降解损害了糖皮质激素受体的反式激活，从而阻止了糖皮质激素的生理活性。然而，抑制蛋白酶体完全恢复了糖皮质激素在氧/葡萄糖剥夺期间稳定血脑屏障的特性。重要的是，在中风后几小时，蛋白酶体抑制剂Bortezomib与类固醇联合治疗的小鼠出现明显较少的脑水肿和功能障碍，而单独治疗无效。结论-我们首次表明抑制蛋白酶体可以克服低氧血脑屏障的糖皮质激素抵抗。因此，联合治疗策略可能有助于对抗未来卒中所致脑水肿的形成，并防止继发性临床恶化。(笔划。2011；42：1081-1089。)
Background and Purpose-Glucocorticoids potently stabilize the blood-brain barrier and ameliorate tissue edema in certain neoplastic and inflammatory disorders of the central nervous system, but they are largely ineffective in patients with acute ischemic stroke. The reasons for this discrepancy are unresolved.Methods-To address the molecular basis for the paradox unresponsiveness of the blood-brain barrier during hypoxia, we used murine brain microvascular endothelial cells exposed to O-2/glucose deprivation as an in vitro model. In an in vivo approach, mice were subjected to transient middle cerebral artery occlusion to induce brain infarctions. Blood-brain barrier damage and edema formation were chosen as surrogate markers of glucocorticoid sensitivity in the presence or absence of proteasome inhibitors.Results-O-2/glucose deprivation reduced the expression of tight junction proteins and transendothelial resistance in murine brain microvascular endothelial cells in vitro. Dexamethasone treatment failed to reverse these effects during hypoxia. Proteasome-dependent degradation of the glucocorticoid receptor impaired glucocorticoid receptor transactivation thereby preventing physiological glucocorticoid activity. Inhibition of the proteasome, however, fully restored the blood-brain barrier stabilizing properties of glucocorticoid during O-2/glucose deprivation. Importantly, mice treated with the proteasome inhibitor Bortezomib in combination with steroids several hours after stroke developed significantly less brain edema and functional deficits, whereas respective monotherapies were ineffective.Conclusions-We for the first time show that inhibition of the proteasome can overcome glucocorticoid resistance at the hypoxic blood-brain barrier. Hence, combined treatment strategies may help to combat stroke-induced brain edema formation in the future and prevent secondary clinical deterioration. (Stroke. 2011;42:1081-1089.)