Zhang Ji-Wei, Liu Jun-Xiu, Hou Hai-Man, Chen Ding-Bang, Feng Li, Wu Chao, Wei Li-Ting, Li Xun-Hua
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Neurology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
Biochem Biophys Res Commun. 2015 Feb 27;458(1):82-5. doi: 10.1016/j.bbrc.2015.01.071. Epub 2015 Jan 26.
Wilson disease is an inherited disorder of excessive copper accumulation. The commonly used drug d-penicillamine (PA) or trientine both cause a high incidence (10-50%) of neurological worsening, which rarely occurs with tetrathiomolybdate (TM) treatment. To investigate the mechanisms of neurologic deterioration after the initiation of chelation therapy, brain hydroxyl radical and free copper were assessed in vivo in this study. On days 3, 7, 14, and 21 after PA or TM administration, striatal hydroxyl radical levels of both TX mice and controls were assessed by terephthalic acid (TA) combined with microdialysis and high-performance liquid chromatography (HPLC). Within the same microdialysis samples, free copper was measured by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that both hydroxyl radical and free copper markedly increased in the striatum of TX mice during PA administration but were not elevated when administering TM. These results suggested that the further increased free copper in the brain and oxidative stress caused by some chelators might contribute to the neurological deterioration.
威尔逊病是一种遗传性疾病，其特征为铜过度蓄积。常用药物d-青霉胺（PA）或曲恩汀均会导致较高比例（10 - 50%）的神经功能恶化，而四硫代钼酸盐（TM）治疗时这种情况很少发生。为了研究螯合治疗开始后神经功能恶化的机制，本研究在体内评估了脑内羟基自由基和游离铜。在给予PA或TM后的第3、7、14和21天，通过对苯二甲酸（TA）结合微透析和高效液相色谱法（HPLC）评估TX小鼠和对照组纹状体中的羟基自由基水平。在相同的微透析样本中，通过电感耦合等离子体质谱法（ICP-MS）测量游离铜。结果显示，在给予PA期间，TX小鼠纹状体中的羟基自由基和游离铜均显著增加，但给予TM时则未升高。这些结果表明，某些螯合剂导致脑内游离铜进一步增加以及氧化应激可能是神经功能恶化的原因。
