Inflachromene ameliorates Parkinson's disease by targeting Nrf2-binding Keap1

Parkinson's disease (PD) is the most common neurodegenerative disease characterized by movement disorder. Despite current therapeutic efforts, PD progression and the loss of dopaminergic neurons in the substantia nigra remain challenging to prevent due to the complex and unclear molecular mecha...

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Published in:Chemical science (Cambridge) 2024-03, Vol.15 (1), p.3588-3595
Main Authors: Yim, Junhyeong, Hwang, Yoon Soo, Lee, Jae-Jin, Kim, Ju Hee, Baek, Jeong Yeob, Jeong, Jaeyeong, Choi, Young Il, Jin, Byung Kwan, Park, Seung Bum
Format: Article
Language:English
Subjects:
Chemistry
Electrophoresis
Glutathione
Neurons
Parkinson's disease
Signs and symptoms
Target recognition
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Summary:Parkinson's disease (PD) is the most common neurodegenerative disease characterized by movement disorder. Despite current therapeutic efforts, PD progression and the loss of dopaminergic neurons in the substantia nigra remain challenging to prevent due to the complex and unclear molecular mechanism involved. We adopted a phenotype-based drug screening approach with neuronal cells to overcome these limitations. In this study, we successfully identified a small molecule with a promising therapeutic effect for PD treatment, called inflachromene (ICM), through our phenotypic screening strategy. Subsequent target identification using fluorescence difference in two-dimensional gel electrophoresis (FITGE) revealed that ICM ameliorates PD by targeting a specific form of Keap1. This interaction led to upregulating various antioxidants, including HO-1, NQO1, and glutathione, ultimately alleviating PD symptoms. Furthermore, ICM exhibited remarkable efficacy in inhibiting the loss of dopaminergic neurons and the activation of astrocytes and microglia, which are critical factors in PD pathology. Our findings suggest that the phenotypic approach employed in this study identified that ICM has potential for PD treatment, offering new hope for more effective therapeutic interventions in the future. Target identification using fluorescence difference in two-dimensional gel electrophoresis (FITGE) revealed the molecular mechanism of ICM that ameliorates PD by targeting a specific form of Keap1.
ISSN:2041-6520
2041-6539
DOI:10.1039/d3sc06997d