Markoutsa Eleni, Xu Peisheng
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina , 715 Sumter Street, Columbia, South Carolina 29208, United States.
Mol Pharm. 2017 May 1;14(5):1591-1600. doi: 10.1021/acs.molpharmaceut.6b01028. Epub 2017 Apr 4.
One hallmark of neuroinflammation is the activation of microglia, which triggers the production and release of reactive oxygen species (ROS), nitrate, nitrite, and cytokines. N-Acetyl cysteine (NAC) is a free radical scavenger that is involved in the intracellular and extracellular detoxification of reactive oxygen species in the brain. However, the clinical application of NAC is limited by its low bioavailability and short half-life. Herein, NAC was conjugated to a polymer through a disulfide bond to form a NAC-prodrug nanoparticle (NAC-NP). Dynamic light scattering found that the NAC-NP has a size of around 50 nm. In vitro studies revealed that the release of NAC from NAC-NP is responsive to its environmental redox potential. For mimicking neuroinflammation in vitro, microglial cells were stimulated by a lipopolysaccharide (LPS), and the effect of NAC-NP on activated microglia was investigated. The study found that the morphology as well as the expression of microgliosis marker Iba-1 of the cells treated with NAC-NPs and LPS were close to those of control cells, indicating that NAC-NPs can inhibit the activation of microglia stimulated by LPS. Compared with free NAC, the production of ROS, NO-, NO-, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β from the LPS-stimulated microglia was considerably decreased when the cells were pretreated with NAC-NPs. Furthermore, LPS-induced microglial phagocytocis of neurons was inhibited in the presence of NAC-NPs. These results indicated that NAC-NPs are more effective than free NAC for reversing the effect of LPS on microglia and subsequently protecting neurons.
神经炎症的一个标志是小胶质细胞的激活，这会触发活性氧（ROS）、硝酸盐、亚硝酸盐和细胞因子的产生与释放。N-乙酰半胱氨酸（NAC）是一种自由基清除剂，参与大脑中活性氧的细胞内和细胞外解毒过程。然而，NAC的临床应用受到其低生物利用度和短半衰期的限制。在此，NAC通过二硫键与一种聚合物偶联，形成NAC前药纳米颗粒（NAC-NP）。动态光散射发现NAC-NP的大小约为50纳米。体外研究表明，NAC从NAC-NP中的释放对其环境氧化还原电位有响应。为了在体外模拟神经炎症，用脂多糖（LPS）刺激小胶质细胞，并研究NAC-NP对活化小胶质细胞的影响。研究发现，用NAC-NPs和LPS处理的细胞的形态以及小胶质细胞增生标志物Iba-1的表达与对照细胞接近，表明NAC-NPs可以抑制LPS刺激的小胶质细胞的激活。与游离NAC相比，当细胞用NAC-NPs预处理时，LPS刺激的小胶质细胞产生的ROS、NO-、NO-、肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-1β显著减少。此外，在存在NAC-NPs的情况下，LPS诱导的小胶质细胞对神经元的吞噬作用受到抑制。这些结果表明，NAC-NPs在逆转LPS对小胶质细胞的影响并随后保护神经元方面比游离NAC更有效。
