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首页> 外文期刊>Experimental Neurology >Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke
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Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke

机译：新型阿司匹林触发的神经保护素D1减轻实验性中风后的脑缺血损伤

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摘要

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 2. h middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24. h, 48. h, 72. h, and 7. days. At 3. h post-stroke onset, an intravenous administration of 333 μg/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 11.7. T 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 24. h, 48. h, 72. h 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.
机译：急性缺血性中风会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）是omega-3必需脂肪酸家族成员，对脑血管疾病具有有益作用。 DHA是神经保护素D1（NPD1）的前体，可下调细胞凋亡，进而促进细胞存活。在这里，我们测试了阿司匹林加DHA的作用，并发现了由阿司匹林触发的NPD1（AT-NPD1）在大脑中的合成。然后，我们对该分子进行了全部化学合成，并在Sprague-Dawley大鼠中2. h脑中动脉闭塞（MCAo）的环境中进行了测试。在24.h，48.h，72.h和7天评估神经系统状态。中风发作后3.小时，静脉注射333μg/ kg的AT-NPD1钠盐（AT-NPD1-SS）或甲酯（AT-NPD1-ME）或媒介物（盐水） 。在第7天，在11.7进行了大脑的离体磁共振成像（MRI）。 MRI。生成了T2WI，3D体积和表观扩散系数（ADC）图。此外，在皮损和纹状体中央病灶处计数梗死体积和GFAP（反应性星形胶质细胞），ED-1（活化的小胶质细胞/巨噬细胞）和SMI-71阳性血管的数量。在MCAo期间和之后，所有动物的直肠和颅温，动脉血气和血浆葡萄糖均显示相似的值。与在24.h，48.h，72.h和7天的盐水治疗相比，AT-NPD1-SS和AT-NPD1-ME的治疗均显着改善了神经学评分。通过AT-NPD1-SS和AT-NPD1-ME处理，皮质中的纹状体（分别减少了44％和81％），纹状体（分别减少了61％和77％）和总梗死（减少了T2WI图像计算的总病变体积）分别为48％和78％）。在盐水组中，由皮质（半影）和纹状体（核心）的T2WI计算出的脑水肿升高。相反，AT-NPD1均在第7天降低了纹状体中的水分。AT-NPD1降低了从T2WI计算得出的3D体积，并且病变大部分位于皮层下区域。使用AT-NPD1-SS和AT-NPD1-ME进行治疗可显着减少皮层梗死体积（分别减少76％和96％），皮层下（分别减少61％和70％）和总梗死体积（分别为69％和84％）根据组织病理学。总之，发现了一种导致大脑中AT-NPD1介体形成的新型生物合成途径。另外，以其钠盐或甲基酯的形式施用合成AT-NPD1能够减轻脑缺血损伤，这导致了一种新的药物干预和临床翻译方法。

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