阻断促炎血小板活化因子受体并激活细胞存活通路：实验性缺血性卒中的一种新治疗策略。
Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke.
作者信息
Belayev Ludmila, Obenaus Andre, Mukherjee Pranab K, Knott Eric J, Khoutorova Larissa, Reid Madigan M, Roque Cassia R, Nguyen Lawrence, Lee Jeong Bin, Petasis Nicos A, Oria Reinaldo B, Bazan Nicolas G
机构信息
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA.
Department of Pediatrics, School of Medicine, University of California, Irvine, USA.
出版信息
Brain Circ. 2020 Dec 29;6(4):260-268. doi: 10.4103/bc.bc_36_20. eCollection 2020 Oct-Dec.
OBJECTIVE
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory, and synaptic alterations. This study explores whether blocking pro-inflammatory platelet-activating factor receptor (PAF-R) plus selected docosanoids after middle cerebral artery occlusion (MCAo) would lead to neurological recovery. The following small molecules were investigated: (a) LAU-0901, a PAF-R antagonist that blocks pro-inflammatory signaling; and (b) derivatives of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and aspirin-triggered NPD1 (AT-NPD1), which activates cell survival pathways and are exert potent anti-inflammatory activity in the brain.
MATERIALS AND METHODS
Sprague-Dawley rats received 2 h MCAo and LAU-0901 (30 or 60 mg/kg, 2 h after stroke), NPD1, and AT-NPD1 (333 μg/kg), DHA (5 mg/kg), and their combination were administered intravenous at 3 h after stroke. Behavior testing and magnetic resonance imaging were conducted on day 3 or 14 to assess lesion characteristics and lipidomic analysis on day 1. Series 1 (LAU-0901 + NPD1, 14d), Series 2 (LAU-0901 + AT-NPD1, 3d), and Series 3 (LAU-0901 + DHA, 1d).
RESULTS
All combinatory groups improved behavior compared to NPD1, AT-NPD1, or DHA treatments alone. Total lesion volumes were reduced with LAU-0901 + NPD1 by 62% and LAU-0901 + AT-NPD1 by 90% treatments versus vehicle groups. LAU-0901 and LAU-0901 + DHA increased the production of vasoactive lipid mediators (prostaglandins: PGE, PGF , 6-keto-PGF , and PGD) as well an inflammatory regulating mediator hydroxyoctadecadienoic acid. In contrast, LAU-0901 and LAU-0901 + DHA decreased the production of 12-hydroxyeicosatetraenoic acid, a pro-inflammatory mediator.
CONCLUSION
Combination therapy with LAU-0901 and selected docosanoids is more effective than the single therapy, affording synergistic neuroprotection, with restored pro-homeostatic lipid mediators and improved neurological recovery. Altogether, our findings support the combinatory therapy as the basis for future therapeutics for ischemic stroke.
目的
急性缺血性中风会引发复杂的神经血管、神经炎症和突触改变。本研究探讨大脑中动脉闭塞（MCAo）后阻断促炎血小板活化因子受体（PAF-R）并联合特定二十二碳六烯酸类化合物是否会促进神经功能恢复。研究了以下小分子化合物：（a）LAU-0901，一种阻断促炎信号传导的PAF-R拮抗剂；（b）二十二碳六烯酸（DHA）的衍生物、神经保护素D1（NPD1）以及阿司匹林触发的NPD1（AT-NPD1），它们可激活细胞存活通路并在大脑中发挥强大的抗炎活性。
材料与方法
将Sprague-Dawley大鼠进行2小时的MCAo手术，然后在中风后2小时静脉注射LAU-0901（30或60mg/kg）、NPD1、AT-NPD1（333μg/kg）、DHA（5mg/kg）以及它们的组合。在第3天或第14天进行行为测试和磁共振成像以评估损伤特征，并在第1天进行脂质组学分析。分为三组：第1组（LAU-0901 + NPD1，14天）、第2组（LAU-0901 + AT-NPD1，3天）和第3组（LAU-0901 + DHA，1天）。
结果
与单独使用NPD1、AT-NPD1或DHA治疗相比，所有联合治疗组的行为均有改善。与对照组相比，LAU-0901 + NPD1治疗使总损伤体积减少了62%，LAU-0901 + AT-NPD1治疗使总损伤体积减少了90%。LAU-0901以及LAU-0901 + DHA增加了血管活性脂质介质（前列腺素：PGE、PGF、6-酮-PGF和PGD）以及炎症调节介质羟基十八碳二烯酸的生成。相反，LAU-0901和LAU-0901 + DHA减少了促炎介质12-羟基二十碳四烯酸的生成。
结论
LAU-0901与特定二十二碳六烯酸类化合物的联合治疗比单一治疗更有效，具有协同神经保护作用，可恢复促稳态脂质介质并改善神经功能恢复。总之，我们的研究结果支持联合治疗作为未来缺血性中风治疗的基础。
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