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Introduction: For investigating the mechanism of brain injury caused by chronic fluorosis, this study was designed to determine whether NRH:quinone oxidoreductase 2 (NQO2) can influence autophagic disruption and oxidative stress induced in the central nervous system exposed to a high level of fluoride. Methods: Sprague–Dawley rats drank tap water containing different concentrations of fluoride for 3 or 6 months. SH-SY5Y cells were either transfected with NQO2 RNA interference or treated with NQO2 inhibitor or activator and at the same time exposed to fluoride. The enrichment of gene signaling pathways related to autophagy was evaluated by Gene Set Enrichment Analysis; expressions of NQO2 and autophagyrelated protein 5 (ATG5), LC3-II and p62, and mammalian target of rapamycin (mTOR) were quantified by Western-blotting or fluorescent staining; and the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) assayed biochemically and reactive oxygen species (ROS) detected by flow cytometry. Results: In the hippocampal CA3 region of rats exposed to high fluoride, the morphological characteristics of neurons were altered; the numbers of autophagosomes in the cytoplasm and the levels of NQO2 increased; the level of p-mTOR was decreased, and the levels of ATG5, LC3-II and p62 were elevated; and genes related to autophagy enriched. In vitro, in addition to similar changes in NQO2, p-mTOR, ATG5, LC3 II, and p62, exposure of SH-SY5Y cells to fluoride enhanced MDA and ROS contents and reduced SOD activity. Inhibition of NQO2 with RNAi or an inhibitor attenuated the disturbance of the autophagic flux and enhanced oxidative stress in these cells exposed to high fluoride. Conclusion: Our findings indicate that NQO2 may be involved in regulating autophagy and oxidative stress and thereby exerts an impact on brain injury caused by chronic fluorosis. [ABSTRACT FROM AUTHOR]

The protective effect of resveratrol (RSV), a stimulator of the silent mating type information regulation 2 homolog (SIRT1), on the neurotoxicity of rat brain induced by chronic fluorosis was investigated. Thirty-two Sprague-Dawley (SD) rats were divided randomly into four groups: (i) a control group; (ii) a RSV treatment group; (iii) a fluoride-exposed group (50 ppm F- in drinking water); and (iv) a fluoride plus RSV group. The experimental period was 7 months. The protein levels of SIRT1 in the cortex and the hippocampus of the rat brains were determined by Western blotting, the SOD activity and the MDA content in the brains by biochemical methods, and the 8-OHdG content by ELISA. The spatial learning ability and the memory of the rats was examined by the Morris Water Maze test. The results showed chronic fluorosis caused changes to the brains of the rats with a reduced SIRT1 protein, elevated MDA and 8-OHdG contents, inhibited SOD activity, and, in addition, decreased learning and memory. Interestingly, RSV pretreatment attenuated the reduced SIRT1, the raised level of oxidative stress, and the lowered ability for learning and memory resulting from the chronic fluorosis. The results indicate that RSV may have a neuroprotective effect on fluoride toxicity. [ABSTRACT FROM AUTHOR]

The protective role of vitamin E (Vit E) against neurotoxicity induced by fluorosis was investigated by using Sprague-Dawley (SD) rats fed with 50 ppm fluoride in drinking water for 10 months. Spatial learning and memory of rats were measured by the Morris water maze test; the expressions of M1 and M3 muscarinic acetylcholine receptors (mAChRs) at the protein level in the hippocampus and cortex were detected by immunohistochemistry; and the levels of O2 ·- and malondiadehyde (MDA) were evaluated by biochemical methods. The results showed that high fluoride inhibited learning ability and memory of the rats, reduced the protein expressions of both M1 and M3 mAChRs, and elevated the levels of O2 ·- and MDA in the rat brains. Interestingly, the treatment of Vit E prevented the increased production of O2 ·- and MDA in brains of the rats fed with high fluoride. In addition, Vit E attenuated the decreased learning ability and memory of the rats exposed to high fluoride, and the mechanism for this may involve the recovered expression of mAChRs resulting from the use of the antioxidant. [ABSTRACT FROM AUTHOR]