Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model. (1st May 2020)

• Record Type: Journal Article
• Authors: Kim, Siwon; Indu Viswanath, Ambily Nath; Park, Jong-Hyun; Lee, Ha Eun; Park, A.Yeong; Choi, Ji Won; Kim, Hyeon Jeong; Londhe, Ashwini M.; Jang, Bo Ko; Lee, Jaeick; Hwang, Hayoung; Lim, Sang Min; Pae, Ae Nim; Park, Ki Duk
• Is Part Of: Neuropharmacology. Volume 167(2020)
• Publication Date: 2020-05-01
• Subjects: Nrf2 activator -- Parkinson's disease -- Nrf2/Keap1 pathway -- Antioxidant -- Anti-inflammation; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.107989
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: Discovery of KKPA4026, a potent Nrf2 activator via interference with Keap1-Nrf2 interaction. KKPA4026 induces Nrf2 nuclear translocation and upregulates the expression of Nrf2-dependent antioxidant enzymes. KKPA4026 reduces the production of inflammatory mediators in an Nrf2-dependent manner. KKPA4026 attenuates PD-associated motor deficits in MPTP-induced mouse model and protects dopaminergic neurons.