Department of Neurology, Hospital for Special Surgery, New York, NY 10021, USA.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Apr;14(3):199-204. doi: 10.3109/17482968.2012.724074. Epub 2012 Sep 17.
The mutated SOD1 protein appears to have a gene dose-dependent effect on the severity and progression of ALS. Lowering of SOD1 protein levels might reduce severity and progression of the disease. The antimalarial drug pyrimethamine (PYR) was identified to cause a dose-dependent reduction in SOD1 protein levels in human cells in vitro. To determine if there was a similar effect in humans, we performed a phase I pilot study in 16 ALS patients with SOD1 mutations, 18 weeks in duration. Blood samples were obtained during all visits. The actin normalized leukocyte SOD1 levels were analyzed using Western blot. SOD1 content in the cerebrospinal fluid (CSF) was determined by ELISA and the SOD1 enzymic activity by spectrophotometric analysis using KO2. Clinical assessment of disease severity was assessed using Appel ALS scale and ALSFRS-R. The leukocyte SOD1 levels showed a significant reduction (p > 0.0001) by the third study visit and this reduction was sustained throughout the remainder of the study. CSF also showed a decrease in SOD1 protein content and enzymic activity in the two patients so tested. Thus, PYR use may be associated with a reduction in SOD1 in ALS patients. The significance is uncertain and further detailed study is required.
突变型 SOD1 蛋白似乎对 ALS 的严重程度和进展具有基因剂量依赖性效应。降低 SOD1 蛋白水平可能会减轻疾病的严重程度和进展。抗疟药物氨苯砜（PYR）被鉴定为在体外人类细胞中导致 SOD1 蛋白水平呈剂量依赖性降低。为了确定在人类中是否存在类似的作用，我们对 16 名携带 SOD1 突变的 ALS 患者进行了为期 18 周的 I 期试点研究。所有就诊时均采集血样。使用 Western blot 分析经肌动蛋白归一化的白细胞 SOD1 水平。通过 ELISA 测定脑脊液（CSF）中的 SOD1 含量，并通过使用 KO2 的分光光度分析测定 SOD1 酶活性。使用 Appel ALS 量表和 ALSFRS-R 评估疾病严重程度的临床评估。白细胞 SOD1 水平在第三次研究就诊时显著降低（p>0.0001），并且这种降低在研究的其余时间内持续存在。在接受测试的两名患者的 CSF 中也观察到 SOD1 蛋白含量和酶活性下降。因此，PYR 的使用可能与 ALS 患者 SOD1 的减少有关。其意义尚不确定，需要进一步详细研究。
