Makola Raymond T, Mbazima Vusi G, Mokgotho Matlou P, Gallicchio Vincent S, Matsebatlela Thabe M
Department of Biochemistry Microbiology and Biotechnology, School of Molecular and Life Sciences, University of Limpopo (Turfloop Campus), Sovenga 0727, South Africa.
Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA.
Int J Inflam. 2020 Jul 25;2020:8340195. doi: 10.1155/2020/8340195. eCollection 2020.
Lithium remains the preferred Food and Drug Administration- (FDA-) approved psychiatric drug for treatment of bipolar disorders since its medical establishment more than half a century ago. Recent studies revealed a promising role for lithium in the regulation of inflammation, oxidative stress, and neurodegeneration unclear about its exact mode of action. Thus, the intention of this study is to delineate the regulatory mechanisms of lithium on oxidative stress in lipopolysaccharide- (LPS-) activated macrophages by evaluating its effects on nuclear factor-B (NF-B) activity and mRNA expression of multiple oxidative stress-related NF-B genes. Raw 264.7 macrophages were treated with up to 10 mM lithium, and no change in cell proliferation, viability, growth, and cell adhesion was observed in real time. Pretreatment with low doses of lithium was shown to reduce nitric oxide (NO) production in LPS-activated macrophages. A reduced internal HDCFDA fluorescence intensity, indicative of reduced reactive oxygen species (ROS) production, was observed in LPS-activated Raw 264.7 macrophages treated with lithium. Lithium has been shown to lower the production of the chemokine RANTES; furthermore, this inhibitory action of lithium has been suggested to be independent of glycogen synthase kinase-3 (GSK3) activity. It is shown here that lithium modulates the expression of several inflammatory genes including IB-, TRAF3, Tollip, and NF-B1/p50 which are regulators of the NF-B pathway. Moreover, lithium inhibits NF-B activity by lowering nuclear translocation of NF-B in LPS-activated macrophages. This is the first study to associate Tollip, Traf-3, and IB- mRNA expression with lithium effect on NF-B activity in LPS-activated Raw 264.7 macrophages. Although these effects were obtained using extratherapeutic concentrations of lithium, results of this study provide useful information towards understanding the mode of action of lithium. This study associates lithium with reduced oxidative stress in LPS-activated Raw 264.7 macrophages and further suggests candidate molecular targets for the regulation of oxidative stress-related diseases using lithium beyond bipolar disorders.
自半个多世纪前被医学认可以来，锂一直是美国食品药品监督管理局（FDA）批准的用于治疗双相情感障碍的首选精神药物。最近的研究表明，锂在调节炎症、氧化应激和神经退行性变方面具有潜在作用，但其确切作用方式尚不清楚。因此，本研究旨在通过评估锂对脂多糖（LPS）激活的巨噬细胞中核因子-κB（NF-κB）活性及多个氧化应激相关NF-κB基因mRNA表达的影响，来阐明锂对氧化应激的调节机制。用高达10 mM的锂处理Raw 264.7巨噬细胞，实时观察到细胞增殖、活力、生长和细胞黏附均无变化。低剂量锂预处理可降低LPS激活的巨噬细胞中一氧化氮（NO）的产生。在用锂处理的LPS激活的Raw 264.7巨噬细胞中，观察到内部HDCFDA荧光强度降低，这表明活性氧（ROS）产生减少。锂已被证明可降低趋化因子RANTES的产生；此外，锂的这种抑制作用被认为独立于糖原合酶激酶-3（GSK3）活性。研究表明，锂可调节包括IκB-α、TRAF3、Tollip和NF-κB1/p50在内的多种炎症基因的表达，这些基因是NF-κB通路的调节因子。此外，锂通过降低LPS激活的巨噬细胞中NF-κB的核转位来抑制NF-κB活性。这是第一项将Tollip、Traf-3和IκB-α mRNA表达与锂对LPS激活的Raw 264.7巨噬细胞中NF-κB活性的影响相关联的研究。尽管这些效应是在使用超治疗浓度的锂时获得的，但本研究结果为理解锂的作用方式提供了有用信息。本研究将锂与LPS激活的Raw 264.7巨噬细胞中氧化应激的降低相关联，并进一步提出了除双相情感障碍外，使用锂调节氧化应激相关疾病的候选分子靶点。
