Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Phytother Res. 2019 Sep;33(9):2256-2273. doi: 10.1002/ptr.6427. Epub 2019 Jul 19.
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a basic-region leucine zipper transcription factor that regulates the expression of many Phase II detoxifying/antioxidant enzymes. Many natural products act on the Nrf2 pathway and exhibit their preventive and/or therapeutic effects by activating Nrf2 and subsequently antioxidant enzymes. In this article, we reviewed the research literature that described Nrf2 activation as a mechanism for the neuroprotective effect of natural products. Our results showed that the inhibition of Kelch-like ECH-associated protein 1 and the activation of different intracellular kinases that lead to Nrf2 phosphorylation were the main mechanisms of Nrf2 upregulation suggested for these the natural products. Although some natural compounds such as terpenoids and alkaloids were reported to protect the nervous system by Nrf2 activating, flavonoids and phenolic compounds represent the majority of the reported neuroprotective natural substances that activate Nrf2. We also evaluated the physiochemical properties of some of the same substances to predict their oral bioavailability and central nervous system penetration. The results showed that sulforaphane and berberine have good oral bioavailability and would be predicted to cross through blood-brain barrier (BBB) easily, whereas the flavonoids in general would be predicted to be less effective in BBB transition because of their relatively high polar surface area.
核因子（红系衍生 2）样 2（Nrf2）是一种碱性亮氨酸拉链转录因子，可调节许多 II 相解毒/抗氧化酶的表达。许多天然产物作用于 Nrf2 途径，并通过激活 Nrf2 及其随后的抗氧化酶来表现出其预防和/或治疗作用。在本文中，我们综述了描述天然产物的 Nrf2 激活作为神经保护作用机制的研究文献。我们的结果表明，Kelch 样 ECH 相关蛋白 1 的抑制和导致 Nrf2 磷酸化的不同细胞内激酶的激活是这些天然产物中上调 Nrf2 的主要机制。尽管一些天然化合物，如萜类和生物碱被报道通过激活 Nrf2 来保护神经系统，但黄酮类和酚类化合物是大多数报道的具有神经保护作用的天然物质，它们可以激活 Nrf2。我们还评估了一些相同物质的物理化学性质，以预测它们的口服生物利用度和对中枢神经系统的穿透性。结果表明，萝卜硫素和小檗碱具有良好的口服生物利用度，并且预计易于穿过血脑屏障（BBB），而黄酮类化合物由于其相对较高的极性表面积，预计在 BBB 转移中效果较差。
