Department of Occupational and Environmental Health, Liaoning Province Key Lab of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, District of Heping, No. 92 North Er Road, Shenyang, 110001, China.
Mediators Inflamm. 2013;2013:895975. doi: 10.1155/2013/895975. Epub 2013 Aug 29.
Excessive fluoride may cause central nervous system (CNS) dysfunction, and oxidative stress is a recognized mode of action of fluoride toxicity. In CNS, activated microglial cells can release more reactive oxygen species (ROS), and NADPH oxidase (NOX) is the major enzyme for the production of extracellular superoxide in microglia. ROS have been characterized as an important secondary messenger and modulator for various mammalian intracellular signaling pathways, including the MAPK pathways. In this study we examined ROS production and TNF- α , IL-1 β inflammatory cytokines releasing, and the expression of MAPKs in BV-2 microglia cells treated with fluoride. We found that fluoride increased JNK phosphorylation level of BV-2 cells and pretreatment with JNK inhibitor SP600125 markedly reduced the levels of intracellular O₂(·-) and NO. NOX inhibitor apocynin and iNOS inhibitor SMT dramatically decreased NaF-induced ROS and NO generations, respectively. Antioxidant melatonin (MEL) resulted in a reduction in JNK phosphorylation in fluoride-stimulated BV-2 microglia. The results confirmed that NOX and iNOS played an important role in fluoride inducing oxidative stress and NO production and JNK took part in the oxidative stress induced by fluoride and meanwhile also could be activated by ROS in fluoride-treated BV-2 cells.
过量的氟化物可能导致中枢神经系统（CNS）功能障碍，氧化应激是氟化物毒性的一种公认作用模式。在 CNS 中，激活的小胶质细胞可以释放更多的活性氧（ROS），而 NADPH 氧化酶（NOX）是小胶质细胞中产生细胞外超氧阴离子的主要酶。ROS 已被确定为各种哺乳动物细胞内信号通路（包括 MAPK 通路）的重要第二信使和调节剂。在这项研究中，我们研究了氟化物处理的 BV-2 小胶质细胞中 ROS 的产生和 TNF-α、IL-1β 炎性细胞因子的释放以及 MAPKs 的表达。我们发现，氟化物增加了 BV-2 细胞 JNK 的磷酸化水平，而 JNK 抑制剂 SP600125 的预处理显著降低了细胞内 O₂(·-)和 NO 的水平。NOX 抑制剂 apocynin 和 iNOS 抑制剂 SMT 分别显著降低了 NaF 诱导的 ROS 和 NO 的产生。抗氧化剂褪黑素（MEL）导致氟化物刺激的 BV-2 小胶质细胞中 JNK 磷酸化减少。结果证实，NOX 和 iNOS 在氟化物诱导的氧化应激和 NO 产生中起重要作用，JNK 参与了氟化物诱导的氧化应激，同时也可以被氟化物处理的 BV-2 细胞中的 ROS 激活。
