College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea.
Neurotox Res. 2019 Jan;35(1):230-243. doi: 10.1007/s12640-018-9951-x. Epub 2018 Aug 31.
We previously reported that desoxo-narchinol A and narchinol B from Nardostachys jatamansi DC (Valerianaceae) inhibited the production of nitric oxide (NO) and prostaglandin E (PGE), and the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 protein in lipopolysaccharide (LPS)-stimulated BV2 and primary microglial cells. In this study, we aimed to elucidate the molecular mechanism underlying the anti-neuroinflammatory effects of desoxo-narchinol A and narchinol B. These two compounds inhibited the nuclear factor (NF)-κB pathway, by repressing the phosphorylation and degradation of inhibitor kappa B (IκB)-α, nuclear translocation of the p65/p50 heterodimer, and DNA-binding activity of the p65 subunit. Furthermore, both compounds induced heme oxygenase-1 (HO-1) protein expression, which was mediated by the activation of nuclear transcription factor erythroid-2-related factor 2 (Nrf2). Activation of the Nrf2/HO-1 pathway by desoxo-narchinol A was shown to be regulated by increased phosphorylation of p38 and extracellular signal-regulated kinase (ERK), whereas only p38 was involved in narchinol B-induced activation of the Nrf2/HO-1 pathway. In addition, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling was also involved in the activation of HO-1 by desoxo-narchinol A and narchinol B. These compounds also increased the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine-9 residue, following phosphorylation of Akt. The anti-neuroinflammatory effect of desoxo-narchinol A and narchinol B was partially blocked by a selective HO-1 inhibitor, suggesting that this effect is partly mediated by HO-1 induction. In addition, both compounds also induced HO-1 protein expression in rat-derived primary microglial cells, which was correlated with their anti-neuroinflammatory effects in LPS-stimulated primary microglial cells. In conclusion, desoxo-narchinol A and narchinol B are potential candidates for the development of preventive agents for the regulation of neuroinflammation in neurodegenerative diseases.
我们之前曾报道过，藏菖蒲中的去氧木香醇 A 和木香醇 B（败酱科）可抑制脂多糖（LPS）刺激的 BV2 和原代小胶质细胞中一氧化氮（NO）和前列腺素 E（PGE）的产生，以及诱导型一氧化氮合酶（iNOS）和环氧化酶（COX）-2 蛋白的表达。在这项研究中，我们旨在阐明去氧木香醇 A 和木香醇 B 的抗神经炎症作用的分子机制。这两种化合物通过抑制 IκB-α 的磷酸化和降解、p65/p50 异二聚体的核易位以及 p65 亚基的 DNA 结合活性来抑制核因子（NF）-κB 途径。此外，这两种化合物都诱导血红素加氧酶-1（HO-1）蛋白的表达，这是由核转录因子红细胞 2 相关因子 2（Nrf2）的激活介导的。去氧木香醇 A 对 Nrf2/HO-1 途径的激活被证明是通过增加 p38 和细胞外信号调节激酶（ERK）的磷酸化来调节的，而只有 p38 参与了木香醇 B 诱导的 Nrf2/HO-1 途径的激活。此外，磷酸肌醇 3-激酶/蛋白激酶 B（PI3K/Akt）信号也参与了去氧木香醇 A 和木香醇 B 对 HO-1 的激活。这两种化合物还增加了丝氨酸 9 位糖原合成酶激酶 3β（GSK3β）的磷酸化，随后 Akt 的磷酸化。去氧木香醇 A 和木香醇 B 的抗神经炎症作用部分被一种选择性的 HO-1 抑制剂阻断，这表明这种作用部分是通过 HO-1 的诱导介导的。此外，这两种化合物还在大鼠原代小胶质细胞中诱导 HO-1 蛋白的表达，这与它们在 LPS 刺激的原代小胶质细胞中的抗神经炎症作用相关。总之，去氧木香醇 A 和木香醇 B 是开发用于调节神经退行性疾病中神经炎症的预防剂的潜在候选药物。
