NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes.
NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes.
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DOI：
10.1007/s10571-023-01363-3
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发表时间：
2023-10
影响因子：
4
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神经保护以减弱或阻断缺血级联反应和挽救神经元损伤已被广泛探索用于治疗缺血性卒中。然而，尽管越来越多的知识，缺血半暗带的生理，机械和影像学特征，没有有效的神经保护therapeutic一直found. This研究的重点是神经保护生物活性的docosanoid介质：神经保护素D1（NPD 1），Resolvin D1（RvD 1），以及它们的组合在实验性中风。NPD 1和RvD 1的分子靶点通过以下剂量-反应和治疗窗来定义。我们证明，NPD 1，RvD 1和联合治疗提供了高级别的神经行为恢复，并减少缺血核心和半影区的体积，即使在中风后6小时内给药。以下基因的表达是显着的：（a）CD 163是一种抗炎性中风相关基因，是NPD 1 + RvD 1差异表达最多的基因，在同病灶半影中显示出超过123倍的上调（Lisi等人，Neurosci Lett 645：106-112，2017）;（B）星形胶质细胞基因PTX 3发生100倍上调，PTX 3是脑缺血后神经发生和血管生成的关键调节因子（. Rodriguez-Grande等人，J Neuroinflammation 12：15，2015）;和（c）Tmem 119和P2 γ 12，两种稳态小胶质细胞的标志物，被发现分别增强了十倍和五倍（步行者等人Int J Mol Sci 21：678，2020）。总的来说，我们发现，大脑中动脉闭塞（MCAo）后，脂质介质的保护作用促进了小胶质细胞和星形胶质细胞特异性基因的表达。（Tmem 119、Fcrls、Osmr、Msr 1、Cd 68、Cd 163、Amigo 2、Thbs 1和Tm 4sf 1）可能参与增强稳态小胶质细胞、调节神经炎症、促进DAMP清除、激活NPC分化和成熟，突触的完整性和有助于细胞存活。在线版本包含补充材料，可通过10.1007/s10571-023-01363-3获得。
Neuroprotection to attenuate or block the ischemic cascade and salvage neuronal damage has been extensively explored for treating ischemic stroke. However, despite increasing knowledge of the physiologic, mechanistic, and imaging characterizations of the ischemic penumbra, no effective neuroprotective therapy has been found. This study focuses on the neuroprotective bioactivity of docosanoid mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination in experimental stroke. Molecular targets of NPD1 and RvD1 are defined by following dose–response and therapeutic window. We demonstrated that treatment with NPD1, RvD1, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes even when administered up to 6 h after stroke. The expression of the following genes was salient: (a) Cd163, an anti-inflammatory stroke-associated gene, was the most differentially expressed gene by NPD1+RvD1, displaying more than a 123-fold upregulation in the ipsilesional penumbra (Lisi et al., Neurosci Lett 645:106–112, 2017); (b) 100-fold upregulation takes place in astrocyte gene PTX3, a key regulator of neurogenesis and angiogenesis after cerebral ischemia (. Rodriguez-Grande et al., J Neuroinflammation 12:15, 2015); and (c) Tmem119 and P2y12, two markers of homeostatic microglia, were found to be enhanced by ten- and fivefold, respectively (Walker et al. Int J Mol Sci 21:678, 2020). Overall, we uncovered that protection after middle cerebral artery occlusion (MCAo) by the lipid mediators elicits expression of microglia and astrocyte-specific genes (Tmem119, Fcrls, Osmr, Msr1, Cd68, Cd163, Amigo2, Thbs1, and Tm4sf1) likely participating in enhancing homeostatic microglia, modulating neuroinflammation, promoting DAMP clearance, activating NPC differentiation and maturation, synapse integrity and contributing to cell survival. The online version contains supplementary material available at 10.1007/s10571-023-01363-3.
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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
影响因子：
8.8
作者：
Androvic, Peter;Kirdajova, Denisa;Valihrach, Lukas
通讯作者：
Valihrach, Lukas
影响因子：
6.3
作者：
Ishrat, Tauheed;Fouda, Abdelrahman Y.;Fagan, Susan C.
通讯作者：
Fagan, Susan C.
影响因子：
2.5
作者：
Connell, Barry J.;Saleh, Monique C.;Saleh, Tarek M.
通讯作者：
Saleh, Tarek M.
影响因子：
16.6
作者：
Fredman, Gabrielle;Hellmann, Jason;Proto, Jonathan D.;Kuriakose, George;Colas, Romain A.;Dorweiler, Bernhard;Connolly, E. Sander;Solomon, Robert;Jones, David M.;Heyer, Eric J.;Spite, Matthew;Tabas, Ira
通讯作者：
Tabas, Ira