Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin.
Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin.
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DOI：
10.3390/antiox11112197
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发表时间：
2022-11-07
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阿尔茨海默病（AD）是最常见的与年龄相关的疾病，没有治疗方法可以预防、延缓、减缓或停止其进展。因此，需要新的药物开发方法。一种有希望的方法是使用表型筛选试验，可以识别在与衰老和认知以及AD病理相关的靶通路中具有治疗功效的化合物。使用这种方法，我们从Yerba santa （Eriodictyon californicum）中鉴定出黄酮甾醇，作为治疗AD的潜在候选药物。Sterubin对激活不同死亡途径的多种细胞死亡启动因子具有高度保护作用，可有效诱导抗氧化转录因子Nrf2，并具有很强的抗炎活性。此外，在阿尔茨海默病的短期模型中，它能够防止短期和长期记忆的下降。为了更好地了解哪些关键的化学官能团对sterubin的有益作用至关重要，我们在表型筛选试验中比较了sterubin与7种密切相关的黄酮类化合物的活性。令人惊讶的是，只有sterubin显示出对多种损伤的有效神经保护活性，以及对几种不同炎症诱导剂的强抗炎活性。这些作用与sterubin在神经和小胶质细胞中强烈诱导Nrf2的能力直接相关。总之，这些结果确定了sterubin的神经保护和抗炎作用的结构要求，并为未来研究基于sterubin的新化合物提供了基础。
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 (Eriodictyon californicum), 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.
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DOI：
10.3390/antiox9100973
发表时间：
2020-10-11
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
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作者：
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Antioxidants (Basel, Switzerland)
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