Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke.
Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke.
复制标题
DOI：
10.1016/j.expneurol.2012.04.007
复制
发表时间：
2012-07
影响因子：
5.3
通讯作者：
Belayev, Ludmila
中科院分区：
文献类型：
--
作者：
Bazan, Nicolas G.;Eady, Tiffany N.;Khoutorova, Larissa;Atkins, Kristal D.;Hong, Song;Lu, Yan;Zhang, Changde;Jun, Bokkyoo;Obenaus, Andre;Fredman, Gabrielle;Zhu, Min;Winkler, Jeremy W.;Petasis, Nicos A.;Serhan, Charles N.;Belayev, Ludmila
关键词：
急性缺血性卒中触发复杂的神经血管、神经炎症和突触改变。阿司匹林和二十二碳六烯酸（DHA），一种ω-3必需脂肪酸家族成员，对脑血管疾病有有益的作用。DHA是神经保护素D1（NPD 1）的前体，NPD 1下调细胞凋亡，进而促进细胞存活。在这里，我们测试了阿司匹林加DHA给药的效果，并发现了阿司匹林触发的NPD 1（AT-NPD 1）在大脑中的合成。然后，我们进行了该分子的全化学合成，并在Sprague-Dawley大鼠大脑中动脉闭塞（MCAo）2小时的情况下进行了测试。在24 h、48 h、72 h和7天时评价神经系统状态。在中风发作后3小时，给予静脉内施用333μg/kg的AT-NPD 1钠盐（AT-NPD 1-SS）或甲酯（AT-NPD 1-ME）或媒介物（盐水）作为治疗。在第7天，在11.7T MRI上进行脑的离体磁共振成像（MRI）。生成T2 WI、3D容积和表观扩散系数（ADC）图。此外，在中央病变水平的皮质和纹状体中对梗死体积和GFAP（反应性星形胶质细胞）、艾德-1（活化的小胶质细胞/巨噬细胞）和SMI-71阳性血管的数量进行计数。在MCAo期间和之后，所有动物的直肠和颅温、动脉血气和血糖值均相似。与盐水处理相比，在24小时、48小时、72小时和7天时，用AT-NPD 1-SS和AT-NPD 1-ME两者处理显著改善神经系统评分。AT-NPD 1-SS和AT-NPD 1-ME治疗显著减少了T2 WI图像计算的皮质（44%和81%）、纹状体（61%和77%）和总梗死（分别为48%和78%）的总病变体积。脑水肿，计算从T2 WI在皮质（半影区）和纹状体（核心），在盐水组升高。相比之下，AT-NPD 1在第7天降低了纹状体中的水含量。根据T2 WI计算的3D体积在AT-NPD 1中均显著减少，并且病变主要位于皮质下区域。用AT-NPD 1-SS和AT-NPD 1-ME两者治疗显著减少皮质（76%和96%）、皮质下（61%和70%）和总（分别为69%和84%）梗死体积，如组织病理学所定义。总之，发现了一种新的生物合成途径，导致在大脑中形成AT-NPD 1介质。此外，施用合成的AT-NPD 1（以其钠盐或甲酯形式）能够减轻脑缺血性损伤，这导致了用于药物干预和临床转化的新方法。
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and synaptic alterations. Aspirin and docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, have beneficial effects on cerebrovascular diseases. DHA is the precursor of neuroprotectin D1 (NPD1), which downregulates apoptosis and, in turn, promotes cell survival. Here we have tested the effect of aspirin plus DHA administration and discovered the synthesis of aspirin-triggered NPD1 (AT-NPD1) in the brain. Then we performed the total chemical synthesis of this molecule and tested in the setting of 2h middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24h, 48h, 72h, and 7 days. At 3h post-stroke onset, an intravenous administration of 333μg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or methyl-ester (AT-NPD1-ME) or vehicle (saline) as treatment was given. On day 7, ex vivo magnetic resonance imaging (MRI) of the brains was conducted on 11.7T MRI. T2WI, 3D volumes, and apparent diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/macrophages) and SMI-71-positive vessels were counted in the cortex and striatum at the level of the central lesion. All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological scores compared to saline treatment at 24h, 48h, 72h and 7 days. Total lesion volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS and AT-NPD1-ME treatment in the cortex (by 44% and 81%), striatum (by 61% and 77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline group. In contrast, both AT-NPD1 decreased water content in the striatum on day 7. 3D volumes, computed from T2WI, were dramatically reduced with both AT-NPD1 and the lesion was mostly localized in the subcortical areas. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%), subcortical (by 61% and 70%) and total (69% and 84%, respectively) infarct volumes as defined by histopathology. In conclusion, a novel biosynthetic pathway that leads to the formation of AT-NPD1 mediator in the brain was discovered. In addition, administration of synthetic AT-NPD1, in either its sodium salt or as the methyl ester, was able to attenuate cerebral ischemic injury which leads to a novel approach for pharmaceutical intervention and clinical translation.
登录
查看更多内容
影响因子：
4.4
作者：
Serhan, CN;Gotlinger, K;Petasis, NA
通讯作者：
Petasis, NA
影响因子：
4.8
作者：
Rowlinson, SW;Crews, BC;Marnett, LJ
通讯作者：
Marnett, LJ
DOI：
10.1073/pnas.0405445101
发表时间：
2004-10-19
影响因子：
11.1
作者：
Chiang, N;Bermudez, EA;Serhan, CN
通讯作者：
Serhan, CN
DOI：
10.1073/pnas.93.6.2317
发表时间：
1996-03-19
影响因子：
11.1
作者：
Kaufmann, WE;Worley, PF;Isakson, P
通讯作者：
Isakson, P
DOI：
10.1097/mco.0b013e32802b7030
发表时间：
2007-03-01
影响因子：
3.1
作者：
Bazan, Nicolas G.
通讯作者：
Bazan, Nicolas G.