Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin
Alzheimer’s disease (AD) is the most frequent age-associated disease with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach is the use of phenotypic screening assays that can identify compounds that have...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/11/11/2197 |
| _version_ | 1797469294124072960 |
|---|---|
| author | Zhibin Liang Pamela Maher |
| author_facet | Zhibin Liang Pamela Maher |
| author_sort | Zhibin Liang |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most frequent age-associated disease with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach is the use of phenotypic screening assays that can identify compounds that have therapeutic efficacy in target pathways relevant to aging and cognition, as well as AD pathology. Using this approach, we identified the flavanone sterubin, from Yerba santa (<i>Eriodictyon californicum</i>), as a potential drug candidate for the treatment of AD. Sterubin is highly protective against multiple initiators of cell death that activate distinct death pathways, potently induces the antioxidant transcription factor Nrf2, and has strong anti-inflammatory activity. Moreover, in a short-term model of AD, it was able to prevent decreases in short- and long-term memory. In order to better understand which key chemical functional groups are essential to the beneficial effects of sterubin, we compared the activity of sterubin to that of seven closely related flavonoids in our phenotypic screening assays. Surprisingly, only sterubin showed both potent neuroprotective activity against multiple insults as well as strong anti-inflammatory activity against several distinct inducers of inflammation. These effects correlated directly with the ability of sterubin to strongly induce Nrf2 in both nerve and microglial cells. Together, these results define the structural requirements underlying the neuroprotective and anti-inflammatory effects of sterubin and they provide the basis for future studies on new compounds based on sterubin. |
| first_indexed | 2024-03-09T19:19:21Z |
| format | Article |
| id | doaj.art-b21fd75cd04246569d659e4d605738c1 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T19:19:21Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-b21fd75cd04246569d659e4d605738c12023-11-24T03:30:50ZengMDPI AGAntioxidants2076-39212022-11-011111219710.3390/antiox11112197Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone SterubinZhibin Liang0Pamela Maher1Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USACellular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, San Diego, CA 92037, USAAlzheimer’s disease (AD) is the most frequent age-associated disease with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach is the use of phenotypic screening assays that can identify compounds that have therapeutic efficacy in target pathways relevant to aging and cognition, as well as AD pathology. Using this approach, we identified the flavanone sterubin, from Yerba santa (<i>Eriodictyon californicum</i>), as a potential drug candidate for the treatment of AD. Sterubin is highly protective against multiple initiators of cell death that activate distinct death pathways, potently induces the antioxidant transcription factor Nrf2, and has strong anti-inflammatory activity. Moreover, in a short-term model of AD, it was able to prevent decreases in short- and long-term memory. In order to better understand which key chemical functional groups are essential to the beneficial effects of sterubin, we compared the activity of sterubin to that of seven closely related flavonoids in our phenotypic screening assays. Surprisingly, only sterubin showed both potent neuroprotective activity against multiple insults as well as strong anti-inflammatory activity against several distinct inducers of inflammation. These effects correlated directly with the ability of sterubin to strongly induce Nrf2 in both nerve and microglial cells. Together, these results define the structural requirements underlying the neuroprotective and anti-inflammatory effects of sterubin and they provide the basis for future studies on new compounds based on sterubin.https://www.mdpi.com/2076-3921/11/11/2197ferroptosisoxytosisinflammationglutathioneAlzheimer’s disease |
| spellingShingle | Zhibin Liang Pamela Maher Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin Antioxidants ferroptosis oxytosis inflammation glutathione Alzheimer’s disease |
| title | Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin |
| title_full | Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin |
| title_fullStr | Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin |
| title_full_unstemmed | Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin |
| title_short | Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin |
| title_sort | structural requirements for the neuroprotective and anti inflammatory activities of the flavanone sterubin |
| topic | ferroptosis oxytosis inflammation glutathione Alzheimer’s disease |
| url | https://www.mdpi.com/2076-3921/11/11/2197 |
| work_keys_str_mv | AT zhibinliang structuralrequirementsfortheneuroprotectiveandantiinflammatoryactivitiesoftheflavanonesterubin AT pamelamaher structuralrequirementsfortheneuroprotectiveandantiinflammatoryactivitiesoftheflavanonesterubin |