A novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, selectively protects against oxidative stress-induced cell death by activating the Nrf2-ARE pathway: Therapeutic implications for ALS
A novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, selectively protects against oxidative stress-induced cell death by activating the Nrf2-ARE pathway: Therapeutic implications for ALS
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DOI：
10.1016/j.freeradbiomed.2012.09.010
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发表时间：
2012-12-01
影响因子：
7.4
通讯作者：
Ikeda, Joh-E
中科院分区：
文献类型：
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作者：
Kanno, Takuya;Tanaka, Kazunori;Ikeda, Joh-E
抗氧化防御是恢复细胞氧化还原动态平衡的关键。最近的研究结果表明，氧化应激在许多神经退行性疾病的发病机制中起着关键作用。因此，抗氧化应激疗法可能是治疗此类疾病的一种有希望的手段。在这项研究中，我们使用了一种新的基于配体的虚拟筛选系统，并发现了一个新的小分子，N-(4-(2-pyridyl)(1，3-thiazol-2-yl))-2-(2，4，6-trimethylphenoxy)乙酰胺(CPn-9)，它以一种不依赖细胞类型的方式选择性地抑制氧化应激诱导的细胞死亡。Cpn-9上调核因子-E2相关因子2(Nrf2)，Nrf2是II期解毒酶和抗氧化蛋白表达的关键转录调节因子，以及Nrf2调节的因子，如血红素氧合酶-1(HO-1)、NAD(P)H-苯二酮氧化还原酶1(NQO1)和谷氨酸-半胱氨酸连接酶修饰亚基(GCLM)。Cpn-9介导的HO-1、NQO1和GCLM上调可被Nrf2基因敲除。此外，抗氧化剂N-乙酰半胱氨酸降低了CPN-9对氧化应激诱导的细胞死亡的保护作用，并伴随着Nrf2核移位的减少。这些结果表明，CPN-9通过激活培养细胞中的Nrf2信号通路而发挥其活性。值得注意的是，Cpn-9在发病后全身应用于携带人类铜锌超氧化物歧化酶(SOD1)基因H46R突变的转基因ALS小鼠模型，维持了运动功能，并延缓了发病后的疾病进展。总而言之，Cpn-9是一种新型的Nrf2激活剂，是治疗包括ALS在内的神经退行性疾病的神经保护候选药物。(C)2012 Elsevier Inc.保留所有权利。
Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders. In this study, we employed a novel ligand-based virtual screening system and identified a novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide (CPN-9), which selectively suppressed oxidative stress-induced cell death in a cell-type-independent manner. CPN-9 upregulates NF-E2-related factor 2 (Nrf2), a key transcriptional regulator of the expression of phase II detoxification enzymes and antioxidant proteins, and Nrf2-regulated factors such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase modifier subunit (GCLM). The CPN-9-mediated upregulation of HO-1, NQO1, and GCLM was abolished by Nrf2 knockdown. Moreover, the antioxidant N-acetylcysteine reduced the proteve effect of CPN-9 against oxidative stress-induced cell death with concomitant diminishing of Nrf2 nuclear translocation. These results indicate that CPN-9 exerts its activity via the reactive oxygen species-dependent activation of the Nrf2 signaling pathway in cultured cells. It is noteworthy that the postonset systemic administration of CPN-9 to a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene sustained motor functions and delayed disease progression after onset. Collectively, CPN-9 is a novel Nrf2 activator and a neuroprotective candidate for the treatment of neurodegenerative diseases, including ALS. (C) 2012 Elsevier Inc. All rights reserved.