Hou Guoqing, Abrams Gerald D, Dick Robert, Brewer George J
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Mich. 48109-0534, USA.
Transl Res. 2008 Nov;152(5):239-44. doi: 10.1016/j.trsl.2008.09.003. Epub 2008 Oct 11.
Tetrathiomolybdate (TM) is a potent anticopper drug developed for Wilson's disease. We have found multiple efficacious results from decreasing copper levels with TM in mouse models of disease, using serum Cp as a surrogate marker of copper status and targeting Cp values of 20% to 50% of baseline. We have found efficacious results of TM therapy in mouse models of fibrosis; inflammation; damage from exogenous agents, such as acetaminophen and doxorubicin; and immune-modulated diseases, such as concanavalin A hepatitis, collagen II-induced arthritis, and the non-obese diabetic (NOD) mouse model of type I diabetes. In the current study, we examine TM efficacy in the EAE mouse model of multiple sclerosis (MS). We find that clinical scores of neurologic damage are significantly inhibited by TM therapy, whether therapy is started before MS-inducing antigen administration or after symptoms from antigen administration develop. Furthermore, we find that experimental autoimmune encephalomyelitis (EAE) treatment produces a marked increase of oxidant damage, as measured by urine isoprostane levels, and TM suppresses these isoprostane increases strongly and significantly. Finally, we find marked increases of inflammatory and immune-related cytokines in this model, and we find that TM strongly and significantly suppresses these increases.
四硫代钼酸盐（TM）是一种为治疗威尔逊氏病而研发的强效抗铜药物。我们在疾病小鼠模型中发现，使用血清铜蓝蛋白（Cp）作为铜状态的替代标志物，并将Cp值设定为基线的20%至50%，用TM降低铜水平可产生多种有效结果。我们还发现TM疗法在纤维化、炎症、对乙酰氨基酚和阿霉素等外源性物质造成的损伤以及免疫调节疾病（如伴刀豆球蛋白A肝炎、胶原II诱导的关节炎和I型糖尿病的非肥胖糖尿病（NOD）小鼠模型）的小鼠模型中均有疗效。在本研究中，我们检测了TM在多发性硬化症（MS）的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中的疗效。我们发现，无论在诱导MS的抗原给药前还是给药后症状出现后开始治疗，TM疗法均能显著抑制神经损伤的临床评分。此外，我们发现，通过尿异前列腺素水平测量，实验性自身免疫性脑脊髓炎（EAE）治疗会使氧化损伤显著增加，而TM能强烈且显著地抑制这些异前列腺素的增加。最后，我们发现该模型中炎症和免疫相关细胞因子显著增加，并且发现TM能强烈且显著地抑制这些增加。
