Department of Occupational and Environmental Health, Research Unit for Toxicology and Chemical Safety Assessment, Institution of Environmental and Health, Major Subject of Environment and Health of Fujian Key Universities, School of Public Health, Fujian Medical University, Jiaotong Road No. 88, Fuzhou, China.
Arch Toxicol. 2012 Nov;86(11):1729-40. doi: 10.1007/s00204-012-0935-y. Epub 2012 Sep 15.
The present study was aimed at determining the role of paraquat (PQ) in the activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and the possible neuroprotective effects of tert-butylhydroquinone (tBHQ) pretreatment on PQ-induced neurodegeneration in vivo and in vitro. 7 mg/kg PQ treatment of male C57BL/6 mice caused decreased spontaneous locomotor activity, decreased tyrosine hydroxylase (TH)-positive neurons, increased terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL)-positive cells in the substantia nigra, as well as increased protein levels of both nuclear Nrf2 and HO-1. In PQ-treated mice, pretreatment with 1 % tBHQ (w/w) significantly attenuated impairments in behavioral performance, decreased TH-positive neurons, and increased TUNEL-positive cells in the substantia nigra, as well as increased protein expression of both nuclear Nrf2 and HO-1. Pretreatment with 40 μM tBHQ protected PC12 cells against 100 and 300 μM PQ-mediated cytotoxicity. The dual-luciferase reporter gene also revealed that the transcriptional activation of HO-1 gene expression of the antioxidant responsive element via Nrf2 occurred as a consequence of 100 and 300 μM PQ exposure. Collectively, these results clearly indicated for the first time that the Nrf2/HO-1 pathway in the substantia nigra was activated by PQ, and pretreatment with tBHQ conferred neuroprotection against PQ-induced Parkinsonism presumably by increasing Nrf2 and HO-1 expression.
本研究旨在确定百草枯（PQ）在激活核因子 E2 相关因子 2（Nrf2）/血红素加氧酶 1（HO-1）通路中的作用，以及叔丁基对苯二酚（tBHQ）预处理对体内和体外 PQ 诱导的神经退行性变的可能神经保护作用。7mg/kg PQ 处理雄性 C57BL/6 小鼠导致自发运动活性降低，酪氨酸羟化酶（TH）阳性神经元减少，黑质中末端脱氧核苷酸转移酶介导的 dUTP 生物素缺口末端标记（TUNEL）阳性细胞增加，以及核 Nrf2 和 HO-1 的蛋白水平增加。在 PQ 处理的小鼠中，1%tBHQ（w/w）预处理显著减轻行为表现受损，减少 TH 阳性神经元，并增加黑质中 TUNEL 阳性细胞，以及核 Nrf2 和 HO-1 的蛋白表达增加。40μM tBHQ 预处理可防止 PC12 细胞受到 100 和 300μM PQ 介导的细胞毒性。双荧光素酶报告基因也表明，抗氧化反应元件的 HO-1 基因表达通过 Nrf2 的转录激活是由于 100 和 300μM PQ 暴露而发生的。总之，这些结果首次清楚地表明，黑质中的 Nrf2/HO-1 通路被 PQ 激活，tBHQ 预处理通过增加 Nrf2 和 HO-1 的表达对 PQ 诱导的帕金森病提供神经保护作用。
