Antipova Veronica, Heimes Diana, Seidel Katharina, Schulz Jennifer, Schmitt Oliver, Holzmann Carsten, Rolfs Arndt, Bidmon Hans-Jürgen, González de San Román Martín Estibaliz, Huesgen Pitter F, Amunts Katrin, Keiler Jonas, Hammer Niels, Witt Martin, Wree Andreas
Institute of Anatomy, Rostock University Medical Center, Rostock, Germany.
Division of Macroscopic and Clinical Anatomy, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
Front Neuroanat. 2024 Jul 16;18:1430790. doi: 10.3389/fnana.2024.1430790. eCollection 2024.
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 displays a rapidly progressing form of Npc1 disease, which is characterized by weight loss, ataxia, and increased cholesterol storage. 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 mice with COMBI, MIGLU or HPßCD resulted in the prevention of body weight loss, reduced total brain weight was not positively influenced.
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.
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 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.
Volumes of brain areas of mice were not specifically changed in terms of functionality after administering COMBI, MIGLU, or HPßCD. Measurements of fresh volumes of brain areas in mice could monitor region-specific changes and response to drug treatment that correlated, in part, with behavioral improvements in this mouse model.
尼曼-匹克病C1型（NPC1，MIM 257220）是一种遗传性溶酶体贮积病，其特征为进行性神经退行性变，可导致残疾和过早死亡。一种小鼠模型表现出快速进展的Npc1病，其特征为体重减轻、共济失调和胆固醇蓄积增加。接受米格鲁司他（MIGLU）、神经甾体别孕烯醇酮（ALLO）和环状寡糖2-羟丙基-β-环糊精（HPßCD）联合治疗（COMBI）的小鼠显示浦肯野细胞损失得到预防、运动功能改善且细胞内脂质蓄积减少。尽管用COMBI、MIGLU或HPßCD治疗小鼠可预防体重减轻，但总脑重减少并未得到积极改善。
为了评估药物治疗引起的不同脑区变化，使用体视学方法测量了假手术和药物治疗的野生型和突变型小鼠各种脑结构的新鲜体积（根据石蜡包埋脑切片确定的体积计算得出的体积）。
在野生型小鼠中，两种治疗方法均未使所研究脑区的体积发生显著变化。与各自的野生型相比，在假手术治疗的小鼠中显著减少的特定脑区的新鲜体积，在所有治疗策略的药物治疗后部分增加；在海马体的CA1区和嗅觉结构中发现了最明显的差异。
给予COMBI、MIGLU或HPßCD后，小鼠脑区的体积在功能方面没有特异性变化。测量小鼠脑区的新鲜体积可以监测区域特异性变化以及对药物治疗的反应，这在一定程度上与该小鼠模型的行为改善相关。
