Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury.
Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury.
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9-叔丁基多西环素对中枢神经系统缺血再灌注损伤天然免疫反应的影响。
DOI：
10.1016/j.yexmp.2020.104601
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发表时间：
2021-03
影响因子：
3.6
通讯作者：
Halterman, Marc W.
中科院分区：
文献类型：
--
作者：
Mai, Nguyen;Knowlden, Sara A.;Miller-Rhodes, Kathleen;Prifti, Viollandi;Sims, Max;Grier, Mark;Nelson, Mark;Halterman, Marc W.
脑缺血触发一系列神经炎性反应和外周免疫反应，导致缺血后再灌注损伤。之前在中枢神经系统缺血模型中进行的工作强调了利用四环素类抗生素的非抗生素特性获得治疗益处的潜力。在本研究中，我们探讨了四环素衍生物9-叔丁基多西环素(9-TB)在模拟心脏骤停后综合征免疫学方面的短暂性全脑缺血小鼠模型中的免疫调节作用。在C57BL/6小鼠身上进行的药代动力学研究表明，在出生后4小时内，大脑中的9-TB水平分别比使用米诺环素和多西环素的水平高1.6倍和9.5倍。米诺环素和9-TB也可以抑制炎症，通过降低小胶质细胞报告系中肿瘤坏死因子α诱导的、依赖于NF-κβ的荧光素酶活性来衡量。值得注意的是，体内缺血再灌注损伤后的每日9-TB治疗诱导了中性粒细胞(PMN)在脾内的滞留，同时使CNS PMN偏向抗炎(CD11bLowYm1High)表型。这些研究表明，除了表现出增强的中枢神经系统递送，9-TB在中枢神经系统缺血-再灌注损伤的背景下改变了PMN的运输和极化。
Cerebral ischemia triggers a cascade of neuroinflammatory and peripheral immune responses that contribute to post-ischemic reperfusion injury. Prior work conducted in CNS ischemia models underscore the potential to harness non-antibiotic properties of tetracycline antibiotics for therapeutic benefit. In the present study, we explored the immunomodulatory effects of the tetracycline derivative 9-tert-butyl doxycycline (9-TB) in a mouse model of transient global ischemia that mimics immunologic aspects of the post-cardiac arrest syndrome. Pharmacokinetic studies performed in C57BL/6 mice demonstrate that within four hours after delivery, levels of 9-TB in the brain were 1.6 and 9.5-fold higher than those obtained using minocycline and doxycycline, respectively. Minocycline and 9-TB also dampened inflammation, measured by reduced TNFα-inducible, NF-κβ-dependent luciferase activity in a microglial reporter line. Notably, daily 9-TB treatment following ischemia-reperfusion injury in vivo induced the retention of polymorphonuclear neutrophils (PMNs) within the spleen while simultaneously biasing CNS PMNs towards an anti-inflammatory (CD11bLowYm1High) phenotype. These studies indicate that aside from exhibiting enhanced CNS delivery, 9-TB alters both the trafficking and polarization of PMNs in the context of CNS ischemia-reperfusion injury.
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影响因子：
82.9
作者：
Benakis C;Brea D;Caballero S;Faraco G;Moore J;Murphy M;Sita G;Racchumi G;Ling L;Pamer EG;Iadecola C;Anrather J
通讯作者：
Anrather J
IL4诱导与抑制神经炎症的体外和体内抑制有关的产生IL6的M2巨噬细胞。
影响因子：
9.3
作者：
Casella G;Garzetti L;Gatta AT;Finardi A;Maiorino C;Ruffini F;Martino G;Muzio L;Furlan R
通讯作者：
Furlan R
影响因子：
6.5
作者：
Grimaldi, D.;Guivarch, E.;Cariou, A.
通讯作者：
Cariou, A.
影响因子：
5.4
作者：
Campbell, Lee A.;Richie, Christopher T.;Harvey, Brandon K.
通讯作者：
Harvey, Brandon K.
影响因子：
37.8
作者：
Adrie, C;Adib-Conquy, M;Cavaillon, JM
通讯作者：
Cavaillon, JM