Key Role of Sulfonylurea Receptor 1 in Progressive Secondary Hemorrhage after Brain Contusion
Key Role of Sulfonylurea Receptor 1 in Progressive Secondary Hemorrhage after Brain Contusion
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DOI：
10.1089/neu.2009.1021
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Gerzanich, Volodymyr
中科院分区：
文献类型：
--
作者：
Simard, J. Marc;Kilbourne, Michael;Gerzanich, Volodymyr
外伤性脑损伤（TBI）的一个重要但鲜为人知的特征是出血性挫伤的时空进展（“开花”）的临床严重问题，我们称之为进行性继发性出血（PSH）。PSH的分子机制尚不清楚，通过促进凝血来减少PSH的努力得到了模棱两可的结果。我们假设PSH可能是由于毛细血管内皮细胞中磺酰脲受体1 （SUR1）调控的NCCa-ATP通道的上调和激活，导致内皮细胞的肿瘤性死亡和毛细血管完整性的灾难性失效。麻醉的成年雄性大鼠进行左顶骨切除术以诱导局灶性皮质挫伤。该通道的调节亚基SUR1在挫伤周围半影组织的毛细血管中显著上调。在未治疗的大鼠中，PSH表现为挫伤深度进行性扩大，深入皮质冲击部位，包括胼胝体、海马和丘脑，外溢血进行性积累，在损伤后的前12小时内体积增加一倍，半影组织毛细血管断裂。使用低剂量（非降糖）格列本脲阻断SUR1在很大程度上消除了PSH和毛细血管破裂，并与坏死灶大小的显著减少和神经行为功能的保存有关。损伤后给予抗SUR1的反义寡脱氧核苷酸可降低SUR1的表达和PSH，这与SUR1转录上调的要求一致。我们的研究结果为PSH与出血性挫伤相关的分子机制提供了新的见解，并指出SUR1是TBI的潜在治疗靶点。
An important but poorly understood feature of traumatic brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming'') of a hemorrhagic contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the contusion. In untreated rats, PSH was characterized by progressive enlargement of the contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic contusions, and point to SUR1 as a potential therapeutic target in TBI.