Institute of Anatomy, University of Rostock, Gertrudenstrasse 9, D-18057 Rostock, Germany.
Neuroscience. 2013 Nov 12;252:201-11. doi: 10.1016/j.neuroscience.2013.08.001. Epub 2013 Aug 13.
Niemann-Pick Type C1 (NPC1) is an autosomal recessive disorder characterized by the accumulation of cholesterol and glycosphingolipids. Combination-treatment utilizing cyclodextrin, allopregnanolone and miglustat (CYCLO/ALLO/miglustat) can ameliorate NPC1 disease in a mutant mouse model. The present study was designed to add behavioral analysis in NPC1 mutant mice upon CYCLO/ALLO/miglustat therapy. NPC1 mutant (BALB/cJ NPC1NIH) and control mice were used. For the combination treatment mice were injected with CYCLO/ALLO weekly, starting at P7. The miglustat injection was performed daily from P10 till P23. Starting at P23, miglustat was added to the powdered chow. For the sham treatment of control and mutant mice the same schedule was used with 0.9% NaCl injection. Locomotor activity was assessed in open field, elevated plus maze and accelerod tests. For assessment of spatial learning and memory the Morris water maze test was conducted. Electron microscopy has been performed to support the behavioral data. The sham-treated mutant mice exhibited motor impairments in all performed tests. In the water maze the sham-treated mutants exhibited impairment in remembering the location of the hidden platform. CYCLO/ALLO/miglustat treatment positively influenced motor dysfunction: total distance and number of visits significantly increased, and accelerod performance improved. The spatial learning, however, did not benefit from therapy. At the morphological level, an excessive accumulation of electron-dense material was seen in the cerebellar Purkinje cells of mutant mice. A regression of these autophagosomal inclusions was seen upon therapy. CYCLO/ALLO/miglustat therapy ameliorates motor but not cognitive deficits in NPC1 mutant mice, suggesting unequal vulnerability of different brain areas to the treatment.
尼曼-匹克 C1 型（NPC1）是一种常染色体隐性疾病，其特征是胆固醇和糖鞘脂的积累。利用环糊精、别孕烯醇酮和米格列醇（CYCLO/ALLO/miglustat）的联合治疗可以改善突变型小鼠 NPC1 疾病。本研究旨在添加 NPC1 突变型小鼠在 CYCLO/ALLO/miglustat 治疗后的行为分析。使用 NPC1 突变型（BALB/cJ NPC1NIH）和对照小鼠。对于联合治疗，从 P7 开始每周给小鼠注射 CYCLO/ALLO。从 P10 到 P23 每天给 miglustat 注射。从 P23 开始，将 miglustat 添加到粉末状饲料中。对于对照和突变型小鼠的假治疗，使用相同的方案，用 0.9%NaCl 注射。在开阔场、高架十字迷宫和加速测试中评估运动活动。为了评估空间学习和记忆，进行了 Morris 水迷宫测试。电子显微镜用于支持行为数据。接受假治疗的突变型小鼠在所有进行的测试中均表现出运动障碍。在水迷宫中，接受假治疗的突变体在记住隐藏平台的位置方面表现出障碍。CYCLO/ALLO/miglustat 治疗对运动功能障碍有积极影响：总距离和访问次数显著增加，加速测试性能提高。然而，空间学习没有受益于治疗。在形态学水平上，突变型小鼠小脑浦肯野细胞中观察到电子致密物质的过度积累。在治疗过程中观察到这些自噬小体包含物的回归。CYCLO/ALLO/miglustat 治疗可改善 NPC1 突变型小鼠的运动障碍，但不能改善认知缺陷，表明不同脑区对治疗的敏感性不同。
