Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Schlegel, Victoria; Thieme, Markus; Holzmann, Carsten; Witt, Martin; Grittner, Ulrike; Rolfs, Arndt; Wree, Andreas

doi:10.3390/ijms17111866

Cited by 16 publications

(25 citation statements)

References 69 publications

(94 reference statements)

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“…Controls included NPC1 +/+ animals as well as NPC1 -/- mutants, being untreated or received normal saline solution or Ringer’s solution without active substances (“sham-treated”). For a better understanding, sham-treated and untreated mice are designated as “sham-treated” in the following sections of this study, since previous studies did not demonstrate any differences between both groups ( Schlegel et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration

Meyer

Gläser

Bräuer

et al. 2018

Front. Integr. Neurosci.

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Background: Neurodegenerative diseases are often accompanied by olfactory deficits. Here we use a rare neurovisceral lipid storage disorder, Niemann–Pick disease C1 (NPC1), to illustrate disease-specific dynamics of olfactory dysfunction and its reaction upon therapy. Previous findings in a transgenic mouse model (NPC1-/-) showed severe morphological and electrophysiological alterations of the olfactory epithelium (OE) and the olfactory bulb (OB) that ameliorated under therapy with combined 2-hydroxypropyl-ß-cyclodextrin (HPßCD)/allopregnanolone/miglustat or HPßCD alone.Methods: A buried pellet test was conducted to assess olfactory performance. qPCR for olfactory key markers and several olfactory receptors was applied to determine if their expression was changed under treatment conditions. In order to investigate the cell dynamics of the OB, we determined proliferative and apoptotic activities using a bromodeoxyuridine (BrdU) protocol and caspase-3 (cas-3) activity. Further, we performed immunohistochemistry and western blotting for microglia (Iba1), astroglia (GFAP) and tyrosine hydroxylase (TH).Results: The buried pellet test revealed a significant olfactory deterioration in NPC1-/- mice, which reverted to normal levels after treatment. At the OE level, mRNA for olfactory markers showed no changes; the mRNA level of classical olfactory receptor (ORs) was unaltered, that of unique ORs was reduced. In the OB of untreated NPC1-/- mice, BrdU and cas-3 data showed increased proliferation and apoptotic activity, respectively. At the protein level, Iba1 and GFAP in the OB indicated increased microgliosis and astrogliosis, which was prevented by treatment.Conclusion: Due to the unique plasticity especially of peripheral olfactory components the results show a successful treatment in NPC1 condition with respect to normalization of olfaction. Unchanged mRNA levels for olfactory marker protein and distinct olfactory receptors indicate no effects in the OE in NPC1-/- mice. Olfactory deficits are thus likely due to central deficits at the level of the OB. Further studies are needed to examine if olfactory performance can also be changed at a later onset and interrupted treatment of the disease. Taken together, our results demonstrate that olfactory testing in patients with NPC1 may be successfully used as a biomarker during the monitoring of the treatment.

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Section: Methodsmentioning

confidence: 99%

Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration

Meyer

Gläser

Bräuer

et al. 2018

Front. Integr. Neurosci.

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“…As previously described by our group [ 45 ] mice of the sham group were injected like those of the combi group at the various time points with respective volumes of 0.9% NaCl or Ringer’s solution, and were fed with chow without drugs. The current dosage regimen was chosen in accordance to previously published studies [ 20 , 21 , 45 , 46 ]. In addition, Tanaka et al [ 19 ] showed that HPβCD applied at a dose of 4000 mg/kg in Npc1 −/− mice caused the best survival rate when compared to saline.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1

Ebner

Gläser

Bräuer

et al. 2018

IJMS

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Niemann–Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1−/− mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.

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“…In addition, the lowering effects on hexosylceramides in WT CHO cells suggest unfavorable actions of miglustat, such as adverse reactions. Schlegel et al [40] reported that treatment with miglustat impairs spatial learning in WT mice compared with a sham group. Further basic and clinical studies to clarify this issue are warranted.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Hoque

Kondo

Sakata

et al. 2020

IJMS

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Niemann–Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.

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Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

Cited by 16 publications

References 69 publications

Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration

Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

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