Journal article
A Novel Analog of the Natural Product Fraxinellone Protects against Endogenous and Exogenous Neurotoxicants
ACS chemical neuroscience, Vol.15(14), pp.2612-2622
07/17/2024
DOI: 10.1021/acschemneuro.4c00090
PMCID: PMC11258694
PMID: 38925635
Appears in UI Libraries Support Open Access
Abstract
Numerous insults, both endogenous (e.g., glutamate) and exogenous (e.g., pesticides), compromise the function of the nervous system and pose risk factors for damage or later disease. In previous reports, limonoids such as fraxinellone showed significant neuroprotective activity against glutamate (Glu) excitotoxicity and reactive oxygen species (ROS) production in vitro, albeit with minimal mechanistic information provided. Given these findings, a library of novel fraxinellone analogs (including analogs 1 and 2 described here) was synthesized with the goal of identifying compounds exhibiting neuroprotection against insults. Analog 2 was found to be protective against Glu-mediated excitotoxicity with a measured EC50 of 44 and 39 nM for in vitro assays using PC12 and SH-SY5Y cells, respectively. Pretreatment with analog 2 yielded rapid induction of antioxidant genes, namely, Gpx4, Sod1, and Nqo1, as measured via qPCR. Analog 2 mitigated Glu-mediated ROS. Cytoprotection could be replicated using sulforaphane (SFN), a Nrf2 activator, and inhibited via ML-385, which inhibits Nrf2 binding to regulatory DNA sequences, thereby blocking downstream gene expression. Nrf2 DNA-binding activity was demonstrated using a Nrf2 ELISA-based transcription factor assay. In addition, we found that pretreatment with the thiol N-acetyl Cys completely mitigated SFN-mediated induction of antioxidant genes but had no effect on the activity of analog 2, suggesting thiol modification is not critical for its mechanism of action. In summary, our data demonstrate a fraxinellone analog to be a novel, potent, and rapid activator of the Nrf2-mediated antioxidant defense system, providing robust protection against insults.Numerous insults, both endogenous (e.g., glutamate) and exogenous (e.g., pesticides), compromise the function of the nervous system and pose risk factors for damage or later disease. In previous reports, limonoids such as fraxinellone showed significant neuroprotective activity against glutamate (Glu) excitotoxicity and reactive oxygen species (ROS) production in vitro, albeit with minimal mechanistic information provided. Given these findings, a library of novel fraxinellone analogs (including analogs 1 and 2 described here) was synthesized with the goal of identifying compounds exhibiting neuroprotection against insults. Analog 2 was found to be protective against Glu-mediated excitotoxicity with a measured EC50 of 44 and 39 nM for in vitro assays using PC12 and SH-SY5Y cells, respectively. Pretreatment with analog 2 yielded rapid induction of antioxidant genes, namely, Gpx4, Sod1, and Nqo1, as measured via qPCR. Analog 2 mitigated Glu-mediated ROS. Cytoprotection could be replicated using sulforaphane (SFN), a Nrf2 activator, and inhibited via ML-385, which inhibits Nrf2 binding to regulatory DNA sequences, thereby blocking downstream gene expression. Nrf2 DNA-binding activity was demonstrated using a Nrf2 ELISA-based transcription factor assay. In addition, we found that pretreatment with the thiol N-acetyl Cys completely mitigated SFN-mediated induction of antioxidant genes but had no effect on the activity of analog 2, suggesting thiol modification is not critical for its mechanism of action. In summary, our data demonstrate a fraxinellone analog to be a novel, potent, and rapid activator of the Nrf2-mediated antioxidant defense system, providing robust protection against insults.
Details
- Title: Subtitle
- A Novel Analog of the Natural Product Fraxinellone Protects against Endogenous and Exogenous Neurotoxicants
- Creators
- Anna E Bartman - University of IowaMersad Raeisi - University of IowaClarence D Peiris - University of IowaIsabella E Jacobsen - University of IowaDavid B C Martin - University of IowaJonathan A Doorn - University of Iowa
- Resource Type
- Journal article
- Publication Details
- ACS chemical neuroscience, Vol.15(14), pp.2612-2622
- Publisher
- American Chemical Society
- DOI
- 10.1021/acschemneuro.4c00090
- PMID
- 38925635
- PMCID
- PMC11258694
- ISSN
- 1948-7193
- eISSN
- 1948-7193
- Language
- English
- Electronic publication date
- 06/26/2024
- Date published
- 07/17/2024
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Chemistry; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984649055402771
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