Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke.
Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke.
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DOI：
10.4103/bc.bc_36_20
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发表时间：
2020-10
影响因子：
1.9
通讯作者：
Bazan NG
中科院分区：
文献类型：
--
作者：
Belayev L;Obenaus A;Mukherjee PK;Knott EJ;Khoutorova L;Reid MM;Roque CR;Nguyen L;Lee JB;Petasis NA;Oria RB;Bazan NG
急性缺血性中风会引发复杂的神经血管、神经炎性和突触改变。本研究探讨阻断促炎症的血小板活化因子受体(PAF-R)加选择性二十二碳二烯类化合物对大脑中动脉闭塞(MCAO)后神经功能恢复的影响。研究了以下小分子：(A)PAF-R拮抗剂LAU-0901，阻断促炎信号；以及(B)二十二碳六烯酸(DHA)、神经保护素D1(NPD1)和阿司匹林触发的NPD1(AT-NPD1)的衍生物，它们激活细胞生存途径，在大脑中具有强大的抗炎活性。SD大鼠于卒中后3h静脉注射N-甲基-D-天门冬氨酸1号(333μg/kg)、DHA(5 mg/kg)及其联合用药。在第3天或第14天进行行为学测试和体外磁共振成像，以评估第1天的病变特征和脂质分析。系列1(LAU-0901+NPD1，14d)、系列2(LAU-0901+AT-NPD1，3D)和系列3(LAU-0901+DHA，1D)。与NPD1、AT-NPD1或DHA单独治疗相比，所有联合治疗组的行为都有所改善。与赋形剂组相比，LAU-0901+NPD1组和LAU-0901+AT-NPD1组的总病变体积分别减少了62%和90%。LAU-0901和LAU-0901+DHA可增加血管活性脂质介质(前列腺素：前列腺素E_2、前列腺素F_2-α、6-酮-前列腺素F_1-α和前列腺素D_2)以及炎症调节介质羟基十八碳二烯酸的产生。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产生。使用LAU-0901和选定的二十二碳二烯类化合物联合治疗比单一治疗更有效，提供了协同的神经保护作用，恢复了有利于体内平衡的脂质介质，并改善了神经功能恢复。综上所述，我们的研究结果支持将综合疗法作为未来治疗缺血性中风的基础。
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. 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 ex vivo 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). 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: PGE2, PGF2-α, 6-keto-PGF1-α, and PGD2) 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. 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.
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DOI：
10.1074/jbc.r117.783076
发表时间：
2017-07-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Asatryan A;Bazan NG
通讯作者：
Bazan NG
DOI：
10.1016/j.bbalip.2014.08.006
发表时间：
2015-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Serhan CN;Dalli J;Colas RA;Winkler JW;Chiang N
通讯作者：
Chiang N
影响因子：
62.1
作者：
Serhan, Charles N.;Petasis, Nicos A.
通讯作者：
Petasis, Nicos A.
DOI：
10.1196/annals.1344.057
发表时间：
2005-01-01
期刊：
NEUROPROTECTIVE AGENTS
影响因子：
--
作者：
Tian, XH;Bazan, NG
通讯作者：
Bazan, NG
影响因子：
5.1
作者：
Bazan, NG
通讯作者：
Bazan, NG