HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.
HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.
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DOI：
10.1016/j.bbi.2018.07.021
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Malm T
中科院分区：
文献类型：
--
作者：
Loppi S;Kolosowska N;Kärkkäinen O;Korhonen P;Huuskonen M;Grubman A;Dhungana H;Wojciechowski S;Pomeshchik Y;Giordano M;Kagechika H;White A;Auriola S;Koistinaho J;Landreth G;Hanhineva K;Kanninen K;Malm T
缺血性中风是死亡和残疾的主要原因之一。现有的治疗方法仅适用于一小部分患者，因此迫切需要新的治疗方法。其中一条脑动脉的阻塞导致大规模和持续的炎症反应，导致附近的神经元损伤。靶向神经炎症的有害途径已被认为是有益的缺血性中风的条件。核受体4A家族（NR 4A）成员Nurr 1已被证明是有害炎症反应的有效调节剂，但Nurr 1在脑卒中中的作用仍不清楚。在这里，我们第一次表明，二聚体转录因子Nurr 1/类维生素A X受体（RXR），HX 600，激动剂，减少小胶质细胞表达的促炎介质，并防止炎症诱导的神经元死亡在体外共培养模型的神经元和小胶质细胞。重要的是，HX 600在永久性大脑中动脉闭塞的小鼠模型中具有保护作用，并减轻中风诱导的运动缺陷。沿着HX 600的体外抗炎能力，用HX 600治疗缺血小鼠减少缺血诱导的Iba-1、p38和TREM 2免疫反应性，保护内源性小胶质细胞免于缺血诱导的死亡，并防止白细胞浸润。这些抗炎功能与脑溶血磷脂酰胆碱（lysoPC）和酰基肉毒碱（与促炎事件相关的代谢物）水平降低有关。这些数据表明，HX 600驱动的Nurr 1激活在缺血性卒中中是有益的，并提出靶向Nurr 1是涉及神经炎症组分的病症的新候选者。
Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
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影响因子：
7.3
作者：
Fonfria, E;Marshall, ICB;McNulty, S
通讯作者：
McNulty, S
DOI：
10.1097/00004647-199607000-00005
发表时间：
1996-07-01
影响因子：
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作者：
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影响因子：
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11
作者：
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影响因子：
8.2
作者：
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