Department of Neurosciences, Psychology, Drug Research and Child Health (Neurofarba), University of Floence, Viale G. Pieraccini 6, 50121 Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Cells. 2024 Oct 4;13(19):1652. doi: 10.3390/cells13191652.
Microglia-mediated neuroinflammation has been linked to neurodegenerative disorders. Inflammation and aging contribute to microglial senescence. Microglial senescence promotes the development of neurodegenerative disorders, including Alzheimer's disease (AD). In this study, we investigated the anti-neuroinflammatory and anti-senescence activity of Honokiol (HNK), a polyphenolic neolignane from Rehder & E.H Wilson, in comparison with its synthetic analogue Honokiol Hexafluoro (CH). HNK reduced the pro-inflammatory cell morphology of LPS-stimulated BV2 microglia cells and increased the expression of the anti-inflammatory cytokine IL-10 with an efficacy comparable to CH. HNK and CH were also able to attenuate the alterations in cell morphology associated with cellular senescence in BV2 cells intermittently stimulated with LPS and significantly reduce the activity and expression of the senescence marker ß-galactosidase and the expression of p21 and pERK1/2. The treatments reduced the expression of senescence-associated secretory phenotype (SASP) factors IL-1ß and NF-kB, decreased ROS production, and abolished H2AX over phosphorylation (γ-H2AX) and acetylated H3 overexpression. Senescent microglia cells showed an increased expression of the Notch ligand Jagged1 that was reduced by HNK and CH with a comparable efficacy to the Notch inhibitor DAPT. Overall, our data illustrate a protective activity of HNK and CH on neuroinflammation and cellular senescence in microglia cells involving a Notch-signaling-mediated mechanism and suggesting a potential therapeutic contribution in aging-related neurodegenerative diseases.
小胶质细胞介导的神经炎症与神经退行性疾病有关。炎症和衰老导致小胶质细胞衰老。小胶质细胞衰老促进了神经退行性疾病的发展，包括阿尔茨海默病（AD）。在这项研究中，我们研究了来自 Rehder & E.H Wilson 的多酚类新木脂素和厚朴酚（HNK）及其合成类似物厚朴酚六氟（CH）的抗神经炎症和抗衰老活性。HNK 降低了 LPS 刺激的 BV2 小胶质细胞的促炎细胞形态，并增加了抗炎细胞因子 IL-10 的表达，其功效可与 CH 相媲美。HNK 和 CH 还能够减轻 LPS 间歇性刺激的 BV2 细胞中与细胞衰老相关的细胞形态改变，并显著降低衰老标志物 ß-半乳糖苷酶的活性和表达以及 p21 和 pERK1/2 的表达。这些治疗方法降低了衰老相关分泌表型（SASP）因子 IL-1ß 和 NF-kB 的表达，减少了 ROS 的产生，并消除了 H2AX 的过度磷酸化（γ-H2AX）和乙酰化 H3 的过度表达。衰老的小胶质细胞表现出 Notch 配体 Jagged1 的表达增加，HNK 和 CH 可降低其表达，其效果可与 Notch 抑制剂 DAPT 相媲美。总体而言，我们的数据说明了 HNK 和 CH 对小胶质细胞中神经炎症和细胞衰老的保护作用，涉及 Notch 信号通路介导的机制，并表明其在与衰老相关的神经退行性疾病中的潜在治疗作用。
