Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan.
Neurosci Res. 2013 Sep-Oct;77(1-2):87-96. doi: 10.1016/j.neures.2013.07.001. Epub 2013 Jul 24.
Activated microglial cells play an important role in immune and inflammatory responses in CNS and play a role in neurodegenerative diseases. We examined the effects of lipoic acid (LA) on inflammatory responses of BV-2 microglial cells activated by lipopolysaccharide (LPS), and explored the underlying mechanisms of action of LA. BV-2 cells treated with LPS showed an up-regulation of mRNA of the pro-inflammatory molecules, inducible nitric oxide synthase (iNOS). LA suppressed the expression of iNOS and furthermore, LPS-induced production of nitrite. Moreover, LA suppressed the nuclear translocation of RelA, a component of nuclear factor-kappa B (NF-κB) that contains transcriptional activator domain for LPS. The mechanisms of LA-mediated anti-inflammatory effects on microglia remain unknown, and we suggested an involvement of Akt/glycogen synthase kinase-3β (GSK-3β) phosphorylation. The results showed that inhibitor of phosphatidylinositol 3-kinase prevented LA-mediated suppression of LPS induction of RelA and expression of iNOS. Furthermore, these inflammatory actions were prevented by GSK-3β inhibitors. These data demonstrate a role for LA as a chemical modulator of inflammatory responses by microglia, and thus may be a therapeutic strategy for treating neurodegenerative diseases with an inflammatory component.
激活的小胶质细胞在中枢神经系统的免疫和炎症反应中发挥重要作用，并在神经退行性疾病中发挥作用。我们研究了硫辛酸 (LA) 对脂多糖 (LPS) 激活的 BV-2 小胶质细胞炎症反应的影响，并探讨了 LA 的作用机制。用 LPS 处理的 BV-2 细胞显示促炎分子诱导型一氧化氮合酶 (iNOS) 的 mRNA 上调。LA 抑制 iNOS 的表达，此外，还抑制 LPS 诱导的亚硝酸盐产生。此外，LA 抑制核因子-κB (NF-κB) 的组成部分 RelA 的核易位，RelA 含有 LPS 的转录激活结构域。LA 对小胶质细胞的抗炎作用的机制尚不清楚，我们认为 Akt/糖原合酶激酶-3β (GSK-3β) 磷酸化参与其中。结果表明，磷脂酰肌醇 3-激酶抑制剂可阻止 LA 介导的 LPS 诱导的 RelA 和 iNOS 表达抑制。此外，这些炎症作用被 GSK-3β 抑制剂所阻止。这些数据表明，LA 作为小胶质细胞炎症反应的化学调节剂发挥作用，因此可能是治疗具有炎症成分的神经退行性疾病的一种治疗策略。
