Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo 27003, Spain.
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo 27003, Spain.
Neuropharmacology. 2018 Oct;141:283-295. doi: 10.1016/j.neuropharm.2018.09.008. Epub 2018 Sep 8.
Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from HO-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of β-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aβ. With the same co-culture trans-well system, the treatment of Aβ-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of AD.
阿尔茨海默病（AD）是一种以淀粉样蛋白-β（Aβ）异常积累和过度磷酸化 tau 为特征的病理学。氧化应激和神经炎症也与这种疾病密切相关。评估了两种新的糖基安卡环酮（streptocyclinones A 和 B，1 和 2）的能力，这些化合物从链霉菌属中分离出来，可以改善 AD 的特征。化合物能够通过激活核因子 E2 相关因子（Nrf2）来保护 SH-SY5Y 神经母细胞瘤细胞免受 HO 诱导的氧化损伤。在脂多糖激活的 BV2 小胶质细胞中测试了它们调节神经炎症的能力。化合物减少了促炎因子的释放，抑制了 NFκB 和有丝分裂原激活的蛋白激酶（MAPK）的激活，并诱导了 Nrf2 向小胶质细胞核的易位。建立了 Trans-well 共培养物来确定用 streptocyclinones 处理的小胶质细胞对 SH-SY5Y 细胞存活的影响。当将化合物添加到 BV2 细胞中时，神经母细胞瘤细胞的细胞活力增加。使用 SH-SY5Y-TMHT441 细胞来确定化合物对 tau 磷酸化的影响。两种化合物都通过靶向 MAPK 激酶减少 tau 过度磷酸化。此外，streptocyclinone B（2）能够抑制 Aβ 刺激的 BV2 细胞中β-分泌酶 1 的活性并减少活性氧的释放。在相同的 Trans-well 共培养物系统中，用化合物 2 处理 Aβ 刺激的小胶质细胞可提高 SH-SY5Y-TMHT441 细胞的活力。本工作中提出的结果提供了这些新的链霉菌化合物显示出多靶标活性的证据，使它们成为 AD 治疗进一步研究的良好候选物。
