Kim, Siwon Viswanath, Ambily Nath Indu 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 2024-01-19T17:33:40Z 2024-01-19T17:33:40Z 2021-09-05 2020-05 0028-3908 https://pubs.kist.re.kr/handle/201004/118683 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. English PERGAMON-ELSEVIER SCIENCE LTD Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model Article 10.1016/j.neuropharm.2020.107989 1 NEUROPHARMACOLOGY, v.167 NEUROPHARMACOLOGY 167 N scie scopus 000528255600023 2-s2.0-85079180831 Neurosciences Pharmacology & Pharmacy Neurosciences & Neurology Pharmacology & Pharmacy Article PROTEIN-PROTEIN INTERACTION TRANSCRIPTION FACTOR NRF2 FUMARIC-ACID ESTERS OXIDATIVE STRESS NEURODEGENERATIVE DISEASES INTERACTION INHIBITOR ALZHEIMERS-DISEASE DISCOVERY NEUROINFLAMMATION EXPRESSION Nrf2 activator Parkinson&apos s disease Nrf2/Keap1 pathway Antioxidant Anti-inflammation