Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1
Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1
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DOI：
10.1111/j.1471-4159.2007.05039.x
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发表时间：
2008-02-01
影响因子：
4.7
通讯作者：
Lipton, Stuart A.
中科院分区：
文献类型：
--
作者：
Satoh, Takumi;Kosaka, Kunio;Lipton, Stuart A.
亲电化合物是一类新发现的具有氧化还原活性的神经保护化合物，其具有缺电子亲电碳中心，通过巯基（S-）烷基化与靶蛋白上的特定半胱氨酸残基反应。虽然植物产生多种生理活性的亲电化合物，但这些化合物的详细作用机制仍然未知。含有邻苯二酚环的化合物已经引起注意，因为它们在氧化时变成亲电醌，尽管它们本身不是亲电的。在这项研究中，我们集中在一个这样的化合物，鼠尾草酸（CA），发现在草药迷迭香从迷迭香获得的神经保护作用。我们发现CA通过与特定的Keap 1半胱氨酸残基结合来激活Keap 1/Nrf 2转录途径，从而保护神经元免受氧化应激和兴奋性毒性。在皮层培养物中，CA-生物素以低浓度在非神经元细胞中积累，以较高浓度在神经元中积累。我们提出的证据表明，神经元和非神经元的CA分布可能有助于其神经保护作用。此外，CA易位到大脑中，在体内增加还原型谷胱甘肽的水平，并保护大脑中动脉缺血/再灌注，这表明CA可能代表一种新型的神经保护亲电化合物。
Electrophilic compounds are a newly recognized class of redox-active neuroprotective compounds with electron deficient, electrophilic carbon centers that react with specific cysteine residues on targeted proteins via thiol (S-)alkylation. Although plants produce a variety of physiologically active electrophilic compounds, the detailed mechanism of action of these compounds remains unknown. Catechol ring-containing compounds have attracted attention because they become electrophilic quinones upon oxidation, although they are not themselves electrophilic. In this study, we focused on the neuroprotective effects of one such compound, carnosic acid (CA), found in the herb rosemary obtained from Rosmarinus officinalis. We found that CA activates the Keap1/Nrf2 transcriptional pathway by binding to specific Keap1 cysteine residues, thus protecting neurons from oxidative stress and excitotoxicity. In cerebrocortical cultures, CA-biotin accumulates in non-neuronal cells at low concentrations and in neurons at higher concentrations. We present evidence that both the neuronal and non-neuronal distribution of CA may contribute to its neuroprotective effect. Furthermore, CA translocates into the brain, increases the level of reduced glutathione in vivo, and protects the brain against middle cerebral artery ischemia/reperfusion, suggesting that CA may represent a new type of neuroprotective electrophilic compound.