Effect of combination therapy consisting of copper and a chelator for Menkes disiease.

由铜和螯合剂组成的联合疗法对门克斯病的效果。

基本信息

批准号：
14570773
负责人：
KODAMA Hiroko
金额：
$ 1.86万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

[Object] Menkes disease is a disorder of copper transport. In patients with Menkes disease, copper accumulates in the intestine, kidney and blood brain barrier (B.B.B.) while the brain remains in a state of copper deficiency. The copper deficiency in the brain cannot be improved by copper injections, because the administered copper accumulates B.B.B. and cannot be transported to neurons. We investigated the effect of combination therapy with administrations of copper and sodium diethyldithiocarbamate (DEDTC), a lypophylic chelator, in the macular mouse.[Methods] Four-week old macular mice that had been treated with 50 ug of CuCl_2 on the 7th day after birth were used. The mice were separated into three groups (group A, chelator + copper ; group B, copper ; group C, saline control). Mice in group A were treated with a subcutaneous injection of CuCl_2 (4 ug) and an intraperitoneal injections of DEDTC (0.2 mg/g) twice a week for 4 weeks and then sacrificed. Mice in group B were treated with only CuCl_22 in the same manner as group A. The brain, kidney and intestine were then dissected, and copper concentration and cytochrome C oxidase (CCO) activity were analyzed.[Results & Conclusions] The copper concentration in the brain of group A was higher than that in group B and C. The CCO activity in the brain was highest in group A. The copper concentrations in the kidneys and intestines of group A were also higher than in group B and C. These results suggest that the chelator enables copper to pass through B.B.B. improving copper deficiency and CCO activity in the brain. However, the combination therapy worsens copper accumulation in the kidney.

[目的]门克斯病是一种铜转运障碍性疾病。在门克斯病患者中，铜积聚在肠道、肾脏和血脑屏障（B.B.B.）中，而大脑仍处于缺铜状态。大脑中的铜缺乏症无法通过注射铜来改善，因为注射的铜会积累 B.B.B.并且不能被输送到神经元。我们研究了给予黄斑小鼠铜和二乙基二硫代氨基甲酸钠（DEDTC）（一种亲脂性螯合剂）联合治疗的效果。[方法] 4周大的黄斑小鼠在治疗后第7天接受50 ug CuCl_2治疗。出生被使用。将小鼠分为三组（A组，螯合剂+铜；B组，铜；C组，盐水对照）。 A组小鼠皮下注射CuCl_2 (4 ug)和腹腔注射DEDTC (0.2 mg/g)，每周两次，持续4周，然后处死。 B组小鼠按照与A组相同的方式仅用CuCl_22处理，然后解剖脑、肾和肠，分析铜浓度和细胞色素C氧化酶(CCO)活性。 [结果与结论] A组大脑中的铜浓度高于B组和C组。A组大脑中的CCO活性最高。A组的肾脏和肠道中的铜浓度也高于B组和C组。这些结果表明螯合剂使铜能够通过 B.B.B.改善大脑中的铜缺乏症和 CCO 活性。然而，联合治疗会恶化肾脏中的铜积累。