文献检索，用中文搜 PubMed

Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia-induced blood-brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia-induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2',4'-trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3-methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin-1/transforming growth factor-β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB-related proteins, ZO-1 and Claudin-5. Conclusions AHR may serve as a potential therapeutic target to attenuate hyperglycemia-induced hematoma expansion and to preserve the BBB in patients with ICH.

背景

高血糖与脑出血（ICH）后血肿扩大（HE）和临床预后恶化有关。然而，强化血糖正常化的临床益处仍存在争议，并且没有批准的治疗方法可减少 HE。芳基烃受体（AHR）已被证明参与了中风后高血糖引起的血脑屏障（BBB）功能障碍和脑损伤。在此，我们研究了 AHR 在雄性 ICH 小鼠模型中高血糖诱导的 HE 中的作用。

方法和结果

本研究使用 CD1 小鼠（n=387）。通过胶原酶注射使小鼠发生 ICH。ICH 后 3 小时经腹腔注射 50%葡萄糖。通过脑室内给予 AHR 敲除簇状规则间隔短回文重复序列来评估 ICH 后 AHR 的作用。ICH 后 2 小时或 6 小时经腹腔给予选择性 AHR 抑制剂 6,2',4'-三甲氧基黄酮进行结局研究。为了评估 AHR 对 HE 的影响，ICH 后 2 小时经腹腔注射 AHR 激动剂 3-甲基胆蒽。结果表明，高血糖性 ICH 上调了 AHR，同时伴有更大的 HE。AHR 抑制通过限制高血糖性 ICH 后的 HE 和保持 BBB 功能提供了神经学益处。体内敲低 AHR 进一步限制了 HE 并增强了 BBB 的完整性。高血糖在体内直接激活 AHR 作为一种生理刺激。在 ICH 后，血小板反应蛋白-1/转化生长因子-β/血管内皮生长因子轴部分参与了 AHR 信号通路，抑制了 BBB 相关蛋白 ZO-1 和 Claudin-5 的表达。