Differently increased volumes of multiple brain areas in Npc1 mutant mice following various drug treatments

Veronica Antipova; Diana Heimes; Katharina Seidel; Jennifer Schulz; Oliver Schmitt; Carsten Holzmann; Arndt Rolfs; Hans-Jürgen Bidmon; Estibaliz González de San Román Martín; Pitter F Huesgen; Katrin Amunts; Jonas Keiler; Niels Hammer; Martin Witt; Andreas Wree

doi:10.3389/fnana.2024.1430790

Differently increased volumes of multiple brain areas in Npc1 mutant mice following various drug treatments

Front Neuroanat. 2024 Jul 16:18:1430790. doi: 10.3389/fnana.2024.1430790. eCollection 2024.

Authors

Veronica Antipova^{1

2}, Diana Heimes^{1

3}, Katharina Seidel^{1

4}, Jennifer Schulz¹, Oliver Schmitt^{1

5}, Carsten Holzmann^{6

7}, Arndt Rolfs⁸, Hans-Jürgen Bidmon^{9

10}, Estibaliz González de San Román Martín^{10

11}, Pitter F Huesgen^{10

12}, Katrin Amunts^{9

13}, Jonas Keiler¹, Niels Hammer^{2

14

15}, Martin Witt^{1

16

17}, Andreas Wree^{1

7}

Affiliations

¹ Institute of Anatomy, Rostock University Medical Center, Rostock, Germany.
² Division of Macroscopic and Clinical Anatomy, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
³ Department of Oral and Maxillofacial Surgery, University Medical Center Mainz, Mainz, Germany.
⁴ Klinik für Frauenheilkunde und Geburtshilfe, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg, Germany.
⁵ Department of Anatomy, Medical School Hamburg, University of Applied Sciences and Medical University, Hamburg, Germany.
⁶ Institute of Medical Genetics, Rostock University Medical Center, Rostock, Germany.
⁷ Centre of Transdisciplinary Neuroscience Rostock, Rostock, Germany.
⁸ Medical Faculty, University of Rostock, Rostock, Germany.
⁹ Institute of Neurosciences and Medicine, Structural and Functional Organisation of the Brain (INM-1), Forschungszentrum Jülich, Jülich, Germany.
¹⁰ Central Institute of Engineering, Electronics and Analytics, ZEA-3, Forschungszentrum Jülich, Jülich, Germany.
¹¹ Centro Joxe Mari Korta, Donostia, Spain.
¹² Institut für Biologie II, AG Funktional Proteomics, Freiburg, Germany.
¹³ C. and O. Vogt Institute for Brain Research, University Hospital Düsseldorf, University Düsseldorf, Düsseldorf, Germany.
¹⁴ Department of Orthopedic and Trauma Surgery, University of Leipzig, Leipzig, Germany.
¹⁵ Division of Biomechatronics, Fraunhofer Institute for Machine Tools and Forming Technology, Dresden, Germany.
¹⁶ Department of Anatomy, Technische Universität Dresden, Dresden, Germany.
¹⁷ Department of Anatomy, Institute of Biostructural Basics of Medical Sciences, Poznan Medical University, Poznan, Poland.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Keywords: 2-hydroxypropyl-β-cyclodextrin; NPC1; brain areas; fresh volumes; lipid storage disorder; miglustat; mouse; treatment.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article This study was supported by the Center of Transdisciplinary Neuroscience Rostock and internal funding as well as by DFG (AM118/7-1).