Organ Weights in NPC1 Mutant Mice Partly Normalized by Various Pharmacological Treatment Approaches

Veronica Antipova; Lisa-Marie Steinhoff; Carsten Holzmann; Arndt Rolfs; Carlos Junior Hempel; Martin Witt; Andreas Wree

doi:10.3390/ijms24010573

Organ Weights in NPC1 Mutant Mice Partly Normalized by Various Pharmacological Treatment Approaches

Int J Mol Sci. 2022 Dec 29;24(1):573. doi: 10.3390/ijms24010573.

Authors

Veronica Antipova^{1

2}, Lisa-Marie Steinhoff¹, Carsten Holzmann^{3

4}, Arndt Rolfs⁵, Carlos Junior Hempel¹, Martin Witt^{1

6}, Andreas Wree^{1

4}

Affiliations

¹ Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany.
² Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Macroscopic and Clinical Anatomy, Medical University of Graz, A-8010 Graz, Austria.
³ Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany.
⁴ Centre of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
⁵ Medical Faculty, University of Rostock, D-18055 Rostock, Germany.
⁶ Department of Anatomy, Technische Universität Dresden, D-01307 Dresden, Germany.

Abstract

Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the NPC1 leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-Npc1^m1N/-J Jackson Npc1 mice in female and male Npc1^+/+ and Npc1^-/- mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 Npc1^+/+, 175 Npc1^-/-) were dissected at P65. In both sexes, the body weights of None and Sham Npc1^-/- mice were lower than those of respective Npc1^+/+ mice. The influence of the Npc1 mutation and/or sex on the weights of various organs, however, differed considerably. In males, Npc1^+/+ and Npc1^-/- mice had comparable absolute weights of lungs, spleen, and adrenal glands. In Npc1^-/- mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female Npc1^-/- mice, ovaries, and uteri were significantly smaller. In Npc1^-/- mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies.

Keywords: 2-hydroxypropyl-β-cyclodextrin; NPC1; allopregnanolone; femur length; gender-specific effects; lipid storage disorder; miglustat; organ weights; organs dimension; stomach volume; treatment effect.

MeSH terms

1-Deoxynojirimycin* / pharmacology
Animals
Body Weight
Cyclodextrins* / pharmacology
Disease Models, Animal
Female
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Niemann-Pick C1 Protein
Niemann-Pick Disease, Type C / drug therapy
Niemann-Pick Disease, Type C / genetics
Organ Size*
Pregnanolone* / pharmacology

Substances

1-Deoxynojirimycin
Cyclodextrins
miglustat
Niemann-Pick C1 Protein
Npc1 protein, mouse
Pregnanolone

Grants and funding

The study was supported by the Center of Transdisciplinary Neuroscience Rostock.