Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Gangwon-do, Republic of Korea.
Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Gangwon-do, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
Phytomedicine. 2021 May;85:153540. doi: 10.1016/j.phymed.2021.153540. Epub 2021 Mar 9.
Neuroinflammation is defined as innate immune system activation in the central nervous system, and is a complex response involved in removing pathogens, toxic components, and dead cells by activating microglial cells. However, over-activated microglia have been implicated in the pathogenesis of neurodegenerative diseases, because they release large amounts of neurotoxic factors. Thus, inhibiting microglial activation may represent an attractive approach for preventing neuroinflammatory disorders. The objective of this study was to investigate the effect of narciclasine (NA) on lipopolysaccharide (LPS)-induced neuroinflammation by evaluating related markers and neurotoxic factors.
BV-2 cells were pre-incubated with NA at 0.1, 0.2, and 0.3 µM for 1h, and then co-treated with LPS for 12 h. Cellular medium and lysates were measured using a nitric oxide assay, enzyme-link immunosorbent assay (ELISA), western blotting, kinase activity assay, luciferase assay, and immunofluorescence assay. C57BL/6N mice were orally administered NA and intraperitoneally injected with LPS, and the cerebral cortex was examined using western blotting and immunofluorescence assays.
NA showed novel pharmacological activity, inhibiting pro-inflammatory factors, including TNF-α, IL-6, IL-18, NO, and PGE, but increasing the anti-inflammatory cytokines IL-10 and TGF-β1 in LPS-induced microglial cells. Moreover, NA also attenuated the LPS-induced mRNA and proteins of iNOS and COX-2. The mechanistic study indicated that NA attenuates the secretion of pro-inflammatory factor by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways, and directly inhibits the catalytic activity of IKKα/β. Furthermore, we found that NA also reduced the expression of the microglial markers Iba-1, COX-2, and TNF-α in the mouse brain.
NA inhibits the over-expression of pro-inflammatory factors but it promotes anti-inflammatory cytokines by down-regulating the Akt/IKK/NF-κB and JNK signaling pathways in experimental models. Thus, NA may be a potential candidate for relieving neuroinflammation.
神经炎症被定义为中枢神经系统固有免疫系统的激活，是一种通过激活小胶质细胞清除病原体、毒性成分和死亡细胞的复杂反应。然而，过度激活的小胶质细胞与神经退行性疾病的发病机制有关，因为它们释放大量神经毒性因子。因此，抑制小胶质细胞的激活可能是预防神经炎症性疾病的一种有吸引力的方法。本研究旨在通过评估相关标志物和神经毒性因子，研究纳曲昔林（NA）对脂多糖（LPS）诱导的神经炎症的影响。
BV-2 细胞先用 0.1、0.2 和 0.3 μM 的 NA 预处理 1 h，然后与 LPS 共同孵育 12 h。用硝酸还原酶法、酶联免疫吸附试验（ELISA）、western blot、激酶活性测定、荧光素酶测定和免疫荧光法测定细胞培养液和细胞裂解液。用 NA 灌胃和 LPS 腹腔注射 C57BL/6N 小鼠，用 western blot 和免疫荧光法检测大脑皮质。
NA 具有抑制 LPS 诱导的小胶质细胞中促炎因子 TNF-α、IL-6、IL-18、NO 和 PGE 的新型药理活性，但增加抗炎细胞因子 IL-10 和 TGF-β1。此外，NA 还减弱了 LPS 诱导的 iNOS 和 COX-2 的 mRNA 和蛋白。机制研究表明，NA 通过下调 Akt/IKK/NF-κB 和 JNK 信号通路抑制促炎因子的分泌，并直接抑制 IKKα/β的催化活性。此外，我们发现 NA 还降低了小鼠大脑中小胶质细胞标志物 Iba-1、COX-2 和 TNF-α的表达。
在实验模型中，NA 通过下调 Akt/IKK/NF-κB 和 JNK 信号通路抑制促炎因子的过度表达，但促进抗炎细胞因子的表达。因此，NA 可能是一种缓解神经炎症的潜在候选药物。
