Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells
Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells
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DOI：
10.1016/j.phrs.2013.07.010
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发表时间：
2013-10-01
影响因子：
9.3
通讯作者：
Motterlini, Roberto
中科院分区：
文献类型：
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作者：
Foresti, Roberta;Bains, Sandip K.;Motterlini, Roberto
核因子红系衍生2相关因子2 （Nrf2）和抗氧化蛋白血红素加氧酶-1 （HO-1）是细胞应激反应的重要组成部分。这两个系统共同对抗氧化应激和炎症，是对抗不同病理（包括神经炎症）的有吸引力的药物靶点。我们的目的是确定最有效的Nrf2/HO-1激活剂，调节小胶质细胞的炎症反应。在本研究中，我们检索了文献，选择了56种据报道可以激活Nrf2或HO-1的化合物，并分析了它们在体外6和24 h对HO-1的诱导作用和对BV2小胶质细胞的细胞毒性。在测试浓度（5-20 μ M）下，大约有20种化合物与鼠油醇、超姜黄素、钴原卟啉- ix和富马酸二甲酯一起上调HO-1，表现出最佳的诱导/低细胞毒性。某些化合物对HO-1的上调导致细胞胆红素水平升高，但不增加血红素合成（ALAS 1）或胆绿素还原酶相关蛋白的表达。HO-1诱导剂产生的胆红素与其抑制干扰素- γ (inf - γ)或脂多糖（LPS）攻击后亚硝酸盐产生的效力相关。与LPS相比，这些化合物在nf - γ激发的细胞中更强烈地下调炎症反应（tnf - α， PGE2和亚硝酸盐），并且用shRNA沉默HO-1或Nrf2对炎症标志物水平的影响有所不同。这些发现表明Nrf2/HO-1的一些小激活剂是小胶质细胞炎症的有效调节剂，并强调了化学支架可以用于合成有效的新衍生物来对抗神经炎症和神经变性。(C) 2013 Elsevier Ltd.版权所有。
The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24 h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 mu M) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Upregulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-gamma (INF-gamma) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-alpha, PGE2 and nitrite) more strongly in cells challenged with INF-gamma than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration. (C) 2013 Elsevier Ltd. All rights reserved.