Liddell Jeffrey R, Lehtonen Sarka, Duncan Clare, Keksa-Goldsteine Velta, Levonen Anna-Liisa, Goldsteins Gundars, Malm Tarja, White Anthony R, Koistinaho Jari, Kanninen Katja M
Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Mental Health Research Institute of Victoria, Parkville, Victoria, Australia.
J Neuroinflammation. 2016 Feb 26;13:49. doi: 10.1186/s12974-016-0515-9.
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.
内源性抗氧化应激防御由核因子红细胞2相关因子2（Nrf2）控制。在疾病过程中，对抗氧化应激的正常补偿机制似乎不足以抵御活性氧的长期暴露。在包括阿尔茨海默病在内的各种涉及氧化应激的疾病模型中，上调Nrf2信号通路以平衡氧化应激的影响已被证明是有效的。通过小分子激活剂刺激Nrf2信号通路是一种上调细胞内源性防御机制的有吸引力的策略。
在此，我们研究金属螯合剂及已知的核因子κB抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）在培养的星形胶质细胞、神经元及小鼠脑中对Nrf2的诱导作用。在与PDTC和激酶抑制剂或β淀粉样蛋白共同处理的培养物以及Nrf2缺陷型培养物中进一步检测Nrf2的诱导情况。
我们发现PDTC是星形胶质细胞中Nrf2信号通路的有效诱导剂，并证明了Nrf2在PDTC介导的抗氧化应激保护中的关键作用。这种诱导似乎受Keap1和糖原合酶激酶3β两者调节。此外，β淀粉样蛋白的存在会放大PDTC介导的内源性保护机制的诱导作用，因此表明PDTC在阿尔茨海默病背景下可能是一种有效的Nrf2诱导剂。最后，我们表明PDTC可增加脑铜含量和血红素加氧酶-1的胶质细胞表达，并在体内降低脂质过氧化，促进形成更具抗氧化性的环境。
PDTC可激活星形胶质细胞而非神经元中的Nrf2及其抗氧化靶点。这些作用可能有助于在阿尔茨海默病模型中观察到的PDTC的神经保护作用。
