Prostaglandin E2 EP2 receptor deletion attenuates intracerebral hemorrhage-induced brain injury and improves functional recovery.
Prostaglandin E2 EP2 receptor deletion attenuates intracerebral hemorrhage-induced brain injury and improves functional recovery.
复制标题
前列腺素E2 EP2受体缺失减弱脑出血引起的脑损伤并改善功能恢复。
DOI：
10.1177/1759091415578713
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发表时间：
2015-03
期刊：
影响因子：
4.7
通讯作者：
Doré S
中科院分区：
文献类型：
--
作者：
Leclerc JL;Lampert AS;Diller MA;Immergluck JB;Doré S
脑出血（ICH）是一种破坏性的中风，其特征是脑实质出血和对血液成分的强烈神经炎症反应导致继发性脑损伤。 ICH 后前列腺素 E2 (PGE2) 的产生显着上调，并部分通过其 E 前列腺素受体亚型 2 (EP2) 促进这种炎症反应。通过 EP2 受体发出的信号已被证明会影响许多急性和慢性神经系统疾病的结果；不过，尚未在 ICH 背景下进行探讨。对野生型 (WT) 和 EP2 受体敲除 (EP2−/−) 小鼠进行 ICH，并分别通过组织学和神经行为测试评估各种解剖和功能结果。与年龄匹配的 WT 对照相比，EP2−/− 小鼠 ICH 引起的脑损伤小了 41.9±4.7%，并且同侧半球增大和脑室内出血的发生率显着减少。解剖学结果与神经功能缺损评分所确定的功能恢复改善相关。进行组织学染色以开始研究 ICH 后 EP2 介导的神经毒性的机制。 EP2−/−小鼠的血液和三价铁积累分别减少了45.5±5.8%和41.4±8.1%。此外，EP2−/− 小鼠的纹状体和皮质小胶质细胞增生、纹状体和皮质星形胶质细胞增生、血脑屏障破坏和外周中性粒细胞浸润明显减少。这项研究首次表明 PGE2-EP2 信号轴在调节 ICH 后的脑损伤、炎症和功能恢复中具有有害作用。靶向 EP2 G 蛋白偶联受体可能代表治疗出血性中风的新治疗途径。
Intracerebral hemorrhage (ICH) is a devastating type of stroke characterized by bleeding into the brain parenchyma and secondary brain injury resulting from strong neuroinflammatory responses to blood components. Production of prostaglandin E2 (PGE2) is significantly upregulated following ICH and contributes to this inflammatory response in part through its E prostanoid receptor subtype 2 (EP2). Signaling through the EP2 receptor has been shown to affect outcomes of many acute and chronic neurological disorders; although, not yet explored in the context of ICH. Wildtype (WT) and EP2 receptor knockout (EP2−/−) mice were subjected to ICH, and various anatomical and functional outcomes were assessed by histology and neurobehavioral testing, respectively. When compared with age-matched WT controls, EP2−/− mice had 41.9 ± 4.7% smaller ICH-induced brain lesions and displayed significantly less ipsilateral hemispheric enlargement and incidence of intraventricular hemorrhage. Anatomical outcomes correlated with improved functional recovery as identified by neurological deficit scoring. Histological staining was performed to begin investigating the mechanisms involved in EP2-mediated neurotoxicity after ICH. EP2−/− mice exhibited 45.5 ± 5.8% and 41.4 ± 8.1% less blood and ferric iron accumulation, respectively. Furthermore, significantly less striatal and cortical microgliosis, striatal and cortical astrogliosis, blood–brain barrier breakdown, and peripheral neutrophil infiltration were seen in EP2−/− mice. This study is the first to suggest a deleterious role for the PGE2-EP2 signaling axis in modulating brain injury, inflammation, and functional recovery following ICH. Targeting the EP2 G protein-coupled receptor may represent a new therapeutic avenue for the treatment of hemorrhagic stroke.