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Published on: June 9, 2017
Ribisins and Certain Analogues Exert Neuroprotective Effects through Activation of the Keap1-Nrf2-ARE Pathway
Shen H Tan1, Muthukumar Karuppasamy2,3, Ping Lan1
1Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632, P. R. China.
Abstract:
Oxidative stress contributes to the pathogenesis of various neurodegenerative diseases and induction of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a validated neuroprotective strategy. Synthetically-derived samples of members of the ribisin class of natural product together with a range of analogues were evaluated for their neuroprotective capacities. Four of the twenty-four compounds tested were found to strongly stimulate antioxidant response element-dependent transcriptional activity in human-derived SH-SY5Y cells. Further, in rat pheochromocytoma PC12 cells and mouse brain cortical cultures these compounds upregulated levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene products, namely heme oxygenase (HO-1) and NAD(P)H quinone reductase 1 (NQO1). Functionally speaking, the compounds conferred protection in these cell models challenged with H2 O2 . In silico molecular modeling suggests that certain of the ribisins can dock in the Nrf2-binding Kelch domain in Keap1, while cysteine labeling by biotinylated iodoacetamide suggest that cysteine residues within Keap1 react with the ribisins. It is thus proposed that the most active compounds exert their neuroprotective activities by targeting Keap1, thereby activating Nrf2 and so increasing transactivation of Nrf2-responsive genes that encode for detoxifying and antioxidant enzymes.
Insights
Natural products called ribisins protect brain cells by activating the Keap1-Nrf2 pathway. These compounds boost antioxidant defenses, offering a potential strategy against neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Oxidative stress is a key factor in neurodegenerative diseases.
- Activating the Keap1-Nrf2 pathway is a proven neuroprotective approach.
Purpose of the Study:
- To evaluate the neuroprotective potential of ribisin natural products and their analogues.
- To investigate the mechanism of action of active ribisin compounds.
Main Methods:
- Testing 24 synthetic ribisin compounds and analogues for neuroprotective activity.
- Utilizing human SH-SY5Y, rat PC12, and mouse cortical cell cultures.
- Employing antioxidant response element (ARE) transcriptional activity assays.
- Measuring nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream gene expression (HO-1, NQO1).
- Conducting in silico molecular modeling and cysteine labeling assays.
Main Results:
- Four ribisin compounds significantly stimulated ARE-dependent transcription in SH-SY5Y cells.
- Active compounds upregulated Nrf2 and its target genes (HO-1, NQO1) in neuronal cells.
- Compounds provided functional protection against hydrogen peroxide-induced oxidative stress.
- Molecular modeling indicated ribisins can bind to Keap1, and cysteine labeling confirmed Keap1 interaction.
Conclusions:
- Certain ribisin compounds exhibit potent neuroprotective effects.
- These compounds likely function by inhibiting Keap1, thereby activating the Nrf2 pathway.
- This mechanism enhances the expression of antioxidant and detoxifying enzymes, offering a novel therapeutic strategy for neurodegenerative conditions.
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