Abstract
Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.
Highlights
Niemann-Pick Type C1 (NPC1) is an autosomal recessive lysosomal storage disease caused by mutations in the NPC1 gene located on chromosomal band 18q11 [1]
Using a battery of standard behavioral tests, we present the first study of pharmacologic effects of miglustat as singularly administered substance in comparison to the well-known combination therapy with β-cyclodextrin/allopregnanolone/miglustat [12] on motor, psychiatric and cognitive capabilities as well as pain sensitivity of wild-type mice
The mice of all groups were weighted on all injection days, i.e., postnatal day 7 (P7) to P63 and before sacrifice, i.e., P67 (Figure 1A)
Summary
Niemann-Pick Type C1 (NPC1) is an autosomal recessive lysosomal storage disease caused by mutations in the NPC1 gene located on chromosomal band 18q11 [1]. The widely used BALB/c-npc1nihNpc1−/− mouse model [3] partly mimics the human disease resulting in neuronal lipid storage and progressive neurodegeneration, seen in a dramatic loss of Purkinje cells [4]. Miglustat administration was shown to slow down the progression of the disease [5]. Miglustat can improve clinical symptoms of NPC1 disease in humans [6,7,8,9] and is well tolerated in NPC1 patients after long-term application [10].
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