Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage
Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage
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DOI：
10.1016/j.phrs.2008.03.004
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发表时间：
2008-05-01
影响因子：
9.3
通讯作者：
Choi, Hyun Jin
中科院分区：
文献类型：
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作者：
Lim, Ju Hee;Kim, Kyeong-Man;Choi, Hyun Jin
帕金森病（PD）是一种与黑质多巴胺能神经元选择性丢失相关的神经退行性疾病。由于多巴胺氧化为多巴胺醌引起的氧化应激被认为是导致PD发病的主要因素，因此诱导催化醌还原的酶NAD（P）H醌氧化还原酶1（NQO 1）可能是保护细胞免受氧化损伤的理想治疗策略。多巴胺激动剂溴隐亭在临床上用于PD治疗。除了通过多巴胺D2受体活化改善运动缺陷外，溴隐亭还具有神经保护和抗氧化活性。在本研究中，我们表明，溴隐亭上调NQO 1的表达和活性，减弱H2 O2处理的PC 12细胞中蛋白结合醌的增加，并保护PC 12细胞免受氧化损伤。溴隐亭增加碱性亮氨酸拉链转录因子核因子E2相关因子2（Nrf 2）的表达和核转位，已知Nrf 2通过抗氧化反应元件参与调节多种抗氧化酶。溴隐亭的Nrf 2相关的细胞保护和抗氧化作用是PI 3 K/Akt通路依赖性的，并且不依赖于多巴胺受体激活。溴隐亭在PC 12细胞中的细胞保护作用不受多巴胺D2拮抗剂的影响，并且在多巴胺D2受体表达的A7-D2和不表达的A7细胞中观察到溴隐亭诱导的Nrf 2-ARE活化和对氧化应激的细胞保护。总之，我们研究了溴隐亭涉及PI 3 K和Nrf 2介导的抗氧化酶NQO 1上调的新型细胞保护作用。(C)2008爱思唯尔有限公司保留所有权利。
Parkinson's disease (PD) is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. Because oxidative stress caused by dopamine oxidation to dopamine quinone is suggested as a major factor contributing to the pathogenesis of PD, the induction of the enzyme that catalyzes the reduction of quinones, NAD(P)H quinone oxidoreductase1 (NQO1), could be a desirable therapeutic strategy to protect cells from oxidative damage. The dopamine agonist bromorcriptine is used clinically for PD therapy. In addition to ameliorating the motor deficit via dopamine D2 receptor activation, bromocriptine also has neuroprotective and antioxidative activity. In the present study, we show that bromocriptine upregulates the expression and activity of NQO1, attenuates the increase in the protein-bound quinone in H2O2-treated PC12 cells, and protects PC12 cells against oxidative damage. Bromocriptine increases the expression and nuclear translocation of a basic leucine zipper transcription factor, nuclear factor-E2-related factor-2 (Nrf2), which is known to be involved in the regulation of numerous antioxidant enzymes via the antioxidant response element. The Nrf2-related cytoprotective and antioxidative effects of bromocriptine are PI3K/Akt pathway-dependent, and are independent of dopamine receptor activation. The cytoprotective effect of bromocriptine in PC12 cells is not affected by the presence of dopamine D2 antagonist, and the bromocriptine-induced Nrf2-ARE activation and cytoprotection against oxidative stress are observed in both dopamine D2 receptor-expressing A7-D2 and non-expressing A7 cells. Taken together, we investigate the novel cytoprotective effect of bromocriptine involving PI3K-and Nrf2-mediated upregulation of the antioxidant enzyme NQO1. (C) 2008 Elsevier Ltd. All rights reserved.