■Niemann-Pick病C1型(NPC1,MIM257220)是一种遗传性溶酶体贮积病,其特征是进行性神经系统变性,导致残疾和过早死亡。Npc1-/-的小鼠模型显示Npc1疾病的快速发展形式,其特点是体重减轻,共济失调,和增加胆固醇储存。Npc1-/-接受miglustat(MIGLU)联合治疗(COMBI)的小鼠,神经类固醇别孕烯醇酮(ALLO)和环状寡糖2-羟丙基-β-环糊精(HPβCD)显示预防浦肯野细胞丢失,改善运动功能,减少细胞内脂质储存。尽管用COMBI治疗Npc1-/-小鼠,MIGLU或HPβCD导致预防体重减轻,减少总脑重量没有积极的影响。
■为了评估药物治疗引起的不同脑区的改变,我们使用体视学方法测量了经过洗发和药物处理的野生型和突变小鼠的各种脑结构的新鲜体积(根据石蜡包埋的脑切片确定的体积计算的体积).
■在野生型小鼠中,两种疗法均未显著改变所研究的脑区体积.与各自的野生型相比,特定大脑区域的新鲜体积,在假治疗的Npc1-/-小鼠中显著降低,在所有治疗策略中,药物治疗后部分增加;在海马CA1区和嗅觉结构中发现了最显著的差异.
■服用COMBI后,Npc1-/-小鼠的脑区体积在功能方面没有特别变化,MIGLU,或HPβCD。Npc1-/-小鼠脑区新鲜体积的测量可以监测区域特异性变化和对药物治疗的反应,在某种程度上,这种小鼠模型的行为改善。
UNASSIGNED: Niemann-Pick disease type C1 (
NPC1, MIM 257220) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. A murine model of
Npc1-/- displays a rapidly progressing form of
Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage.
Npc1-/- mice receiving a combined therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) showed prevention of Purkinje cell loss, improved motor function and reduced intracellular lipid storage. Although therapy of
Npc1-/- mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced.
UNASSIGNED: In order to evaluate alterations of different brain areas caused by pharmacotherapy, fresh volumes (volumes calculated from the volumes determined from paraffin embedded brain slices) of various brain structures in sham- and drug-treated wild type and mutant mice were measured using stereological methods.
UNASSIGNED: In the wild type mice, the volumes of investigated brain areas were not significantly altered by either therapy. Compared with the respective wild types, fresh volumes of specific brain areas, which were significantly reduced in sham-treated Npc1-/- mice, partly increased after the pharmacotherapies in all treatment strategies; most pronounced differences were found in the CA1 area of the hippocampus and in olfactory structures.
UNASSIGNED: Volumes of brain areas of
Npc1-/- mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in Npc1-/- mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model.