Substrate reduction intervention by L-cycloserine in Twitcher Mice (globoid cell leukodystrophy) on a B6;CAST/Ei background
Substrate reduction intervention by L-cycloserine in Twitcher Mice (globoid cell leukodystrophy) on a B6;CAST/Ei background
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DOI：
10.1016/s0304-3940(03)00633-5
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发表时间：
2003-08-14
影响因子：
2.5
通讯作者：
LeVine, SM
中科院分区：
文献类型：
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作者：
Biswas, S;Biesiada, H;LeVine, SM
球样细胞脑白质营养不良（GCL）通常是由半乳糖神经酰胺酶突变引起的致命性脱髓鞘疾病，半乳糖神经酰胺酶通常使半乳糖神经酰胺（髓鞘的主要糖脂）和精神分裂素（psychosine）分解。最初的病理学被认为是由于精神分裂素在髓鞘形成细胞中的积累导致其死亡。在这项研究中，底物减少治疗使用L-环丝氨酸，3-酮二氢鞘氨醇合酶的抑制剂，在抽搐小鼠C57 BL/6 x CAST/Ei（B6;CAST/Ei）的背景下，这模拟了GCL的晚发型变异。在症状出现之前开始的L-环丝氨酸的分级剂量方案使寿命增加了约45%，并延迟了体重减轻的发生，而在症状出现之后开始的L-环丝氨酸给药则没有效果。尽管早期治疗方案效果显著，但B6;CAST/Ei tickcher小鼠仍表现出导致早期死亡的进行性疾病。(C)2003爱思唯尔科学爱尔兰有限公司保留所有权利。
Globoid cell leukodystrophy (GCL) is usually a fatal demyelinating disease caused by mutations in galactosylceramidase, which normally recycles galactosylceramide, a predominant glycolipid of myelin, and psychosine. The initial pathology is thought to be due to the accumulation of psychosine in myelin-forming cells leading to their death. In this study, substrate reduction therapy using L-cycloserine, an inhibitor of 3-ketodihydrosphingosine synthase, was examined in twitcher mice on a C57BL/6 x CAST/Ei (B6;CAST/Ei) background, which mimics a late onset variant of GCL. A graded dose regimen Of L-cycloserine initiated before the onset of symptoms increased the lifespan by similar to45% and delayed the onset of weight loss while the administration of L-cycloserine beginning after the onset of symptoms had no effect. Despite the pronounced effect for the early treatment regimen, B6;CAST/Ei twitcher mice still displayed a progressive disease leading to an early death. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.