Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes.
Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes.
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DOI：
10.1186/s12974-016-0515-9
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发表时间：
2016-02-26
影响因子：
9.3
通讯作者：
Kanninen KM
中科院分区：
文献类型：
--
作者：
Liddell JR;Lehtonen S;Duncan C;Keksa-Goldsteine V;Levonen AL;Goldsteins G;Malm T;White AR;Koistinaho J;Kanninen KM
内源性氧化应激防御是由核因子红细胞2相关因子2 （Nrf2）控制的。对抗氧化应激的正常代偿机制似乎不足以防止疾病期间长时间暴露于活性氧。通过上调Nrf2信号来平衡氧化应激的影响已被证明在包括阿尔茨海默病在内的多种涉及氧化应激的疾病模型中有效。通过小分子激活剂刺激Nrf2信号是上调细胞内源性防御机制的一种有吸引力的策略。在此，我们研究了金属螯合剂和已知的核因子-κB抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）在培养的星形胶质细胞、神经元和小鼠脑中的Nrf2诱导作用。在PDTC和激酶抑制剂或β淀粉样蛋白共同处理的培养物中，以及Nrf2缺失培养物中，Nrf2的诱导作用得到了进一步的研究。我们发现PDTC是星形胶质细胞中Nrf2信号的有效诱导剂，并证明Nrf2在PDTC介导的抗氧化应激保护中起着关键作用。这种诱导似乎受到Keap1和糖原合成酶激酶3β的调节。此外，β淀粉样蛋白的存在放大了PDTC介导的内源性保护机制的诱导，因此表明PDTC可能是阿尔茨海默病背景下有效的Nrf2诱导剂。最后，我们发现PDTC增加脑铜含量和血红素氧化酶-1的胶质表达，减少体内脂质过氧化，促进更抗氧化的环境。PDTC在星形胶质细胞中激活Nrf2及其抗氧化靶点，而不是神经元。这些作用可能有助于在阿尔茨海默病模型中观察到PDTC的神经保护作用。本文的在线版本（doi:10.1186/s12974-016-0515-9）包含补充材料，可供授权用户使用。
Endogenous defense against oxidative stress is controlled by nuclear factor erythroid 2-related factor 2 (Nrf2). The normal compensatory mechanisms to combat oxidative stress appear to be insufficient to protect against the prolonged exposure to reactive oxygen species during disease. Counterbalancing the effects of oxidative stress by up-regulation of Nrf2 signaling has been shown to be effective in various disease models where oxidative stress is implicated, including Alzheimer’s disease. Stimulation of Nrf2 signaling by small-molecule activators is an appealing strategy to up-regulate the endogenous defense mechanisms of cells. Here, we investigate Nrf2 induction by the metal chelator and known nuclear factor-κB inhibitor pyrrolidine dithiocarbamate (PDTC) in cultured astrocytes and neurons, and mouse brain. Nrf2 induction is further examined in cultures co-treated with PDTC and kinase inhibitors or amyloid-beta, and in Nrf2-deficient cultures. We show that PDTC is a potent inducer of Nrf2 signaling specifically in astrocytes and demonstrate the critical role of Nrf2 in PDTC-mediated protection against oxidative stress. This induction appears to be regulated by both Keap1 and glycogen synthase kinase 3β. Furthermore, the presence of amyloid-beta magnifies PDTC-mediated induction of endogenous protective mechanisms, therefore suggesting that PDTC may be an effective Nrf2 inducer in the context of Alzheimer’s disease. Finally, we show that PDTC increases brain copper content and glial expression of heme oxygenase-1, and decreases lipid peroxidation in vivo, promoting a more antioxidative environment. PDTC activates Nrf2 and its antioxidative targets in astrocytes but not neurons. These effects may contribute to the neuroprotection observed for PDTC in models of Alzheimer’s disease. The online version of this article (doi:10.1186/s12974-016-0515-9) contains supplementary material, which is available to authorized users.