Genetic deletion of the prostaglandin E2 E prostanoid receptor subtype 3 improves anatomical and functional outcomes after intracerebral hemorrhage.
Genetic deletion of the prostaglandin E2 E prostanoid receptor subtype 3 improves anatomical and functional outcomes after intracerebral hemorrhage.
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DOI：
10.1111/ejn.12909
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Doré S
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文献类型：
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作者：
Leclerc JL;Lampert AS;Diller MA;Doré S
脑出血（ICH）是一种高死亡率和高发病率的脑卒中亚型。脑出血后，兴奋性毒性和炎症显著导致继发性脑损伤和不良预后。前列腺素E2 （PGE2）水平随着神经系统的损伤而局部升高，已知PGE2主要通过其E前列腺素受体EP1-4调节这些过程。EP3是大脑中最丰富的EP受体，我们之前已经表明，通过PGE2-EP3轴的信号传导加剧了兴奋性毒性和缺血性卒中的结果。本研究旨在探讨该通路在脑出血后调节解剖结果和功能恢复中的作用。通过神经功能缺损评分，EP3受体基因缺失使ich所致脑损伤减少48.2±7.3% (p < 0.005)，功能恢复改善（p < 0.05）。为了开始研究与PGE2-EP3信号受损有关的神经保护机制，我们进行了组织学染色来评估血液和铁积累、神经炎症、血脑屏障功能障碍和外周中性粒细胞浸润。脑出血后，EP3−/−小鼠血量减少49.5±8.8% (p < 0.01)，三铁含量减少42.8±13.1% （p < 0.05）。此外，EP3−/−小鼠的星形胶质细胞增生、小胶质细胞活化、血脑屏障破坏和中性粒细胞浸润显著减少。综上所述，这些结果表明PGE2-EP3信号轴在脑出血后脑损伤、炎症和神经功能恢复的调节中具有损伤作用。调节PGE2-EP3信号轴可能是治疗脑出血的一种假定的治疗途径。
Intracerebral hemorrhage (ICH) is a stroke subtype associated with high mortality and morbidity. Following ICH, excitotoxicity and inflammation significantly contribute to secondary brain injury and poor outcomes. Prostaglandin E2 (PGE2) levels rise locally with insult to the nervous system, and PGE2 is known to modulate these processes mainly through its E prostanoid (EP) receptors, EP1–4. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates excitotoxicity and ischemic stroke outcomes. This study aimed to investigate the contribution of this pathway in modulating anatomical outcomes and functional recovery following ICH. Genetic deletion of the EP3 receptor resulted in 48.2 ± 7.3% less ICH-induced brain injury (p < 0.005) and improved functional recovery (p < 0.05), as identified by neurological deficit scoring. To start investigating the mechanisms involved in neuroprotection with impaired PGE2-EP3 signaling, histological staining was performed to evaluate blood and ferric iron accumulation, neuroinflammation, blood brain barrier dysfunction, and peripheral neutrophil infiltration. After ICH, EP3−/− mice demonstrated 49.5 ± 8.8% and 42.8 ± 13.1% less blood (p < 0.01) and ferric iron content (p < 0.05), respectively. Furthermore, EP3−/− mice had significantly reduced astrogliosis, microglial activation, blood brain barrier breakdown, and neutrophil infiltration. Collectively, these results suggest an injurious role for the PGE2-EP3 signaling axis in modulating brain injury, inflammation, and neurologic functional recovery after ICH. Modulation of the PGE2-EP3 signaling axis may represent a putative therapeutic avenue for the treatment of ICH.