Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Neuropharmacology. 2020 May 1;167:107989. doi: 10.1016/j.neuropharm.2020.107989. Epub 2020 Feb 5.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.
帕金森病（PD）是一种神经退行性疾病，其特征是运动异常，包括运动迟缓、拖曳步态、缺乏平衡和震颤。氧化应激已被证明在 PD 中多巴胺能神经元细胞死亡中起决定性作用。核因子 E2 相关因子 2（Nrf2）-Kelch 样 ECH 相关蛋白 1（Keap1）信号通路通过诱导抗氧化酶基因的表达提供了对抗氧化应激的主要防御系统。直接干扰 Keap1-Nrf2 蛋白-蛋白相互作用（PPI）已成为激活 Nrf2 的有效策略。因此，我们使用虚拟筛选方法寻找可以破坏 Nrf2-Keap1 相互作用的新型 Nrf2 激活剂，并鉴定出一种有效的 Nrf2 激活剂 KKPA4026。KKPA4026 被证实可诱导 BV-2 细胞中 Nrf2 依赖性抗氧化酶血红素加氧酶-1、谷氨酸-半胱氨酸连接酶催化亚基、谷氨酸-半胱氨酸连接酶调节亚基和 NAD（P）H：醌氧化还原酶 1 的表达。此外，KKPA4026 以 Nrf2 依赖性方式表现出抗炎作用。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中，KKPA4026 有效减轻 PD 相关行为缺陷并保护多巴胺能神经元。总之，我们鉴定出 KKPA4026 是一种新型的 Nrf2 激活剂，并提出通过干扰 Nrf2-Keap1 相互作用激活 Nrf2 可能对 PD 治疗有效。
