Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

Abstract

In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1−/− mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1−/− and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1−/− mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1−/− mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1−/− mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1−/− mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1−/− mice was almost completely reduced only in the female groups.

Peripheral immune system modulates Purkinje cell degeneration in Niemann–Pick disease type C1

“…Gender-specific differences in the cerebellar Purkinje cell degeneration have been previously reported in NPC1 (Võikar et al, 2002;Holzmann et al, 2021), heterozygous staggerer (Lemaigredubreuil et al, 1999), and reeler mice (Hadj-Sahraoui et al, 1996). In these studies, the Purkinje cell loss and the related behavioral abnormalities were more severe in male than female mice; facts are consistent with our current observation.…”

Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

“…Indeed, allopregnanolone levels are found decreased in NPC [95]. The beneficial effects of allopregnanolone on dysmyelination, alone or in combination with HPβCD and miglustat, have been extensively investigated in NPC mice [95,97,98]. Specifically, the administration of allopregnanolone solubilized in HPβCD to NPC mice was effective in delaying clinical onset, extending lifespan, and reducing ganglioside accumulation [95]; moreover, this treatment also normalized myelin content in the corpus callosum and hippocampus measured by DTI [89].…”

Curcumin Has Beneficial Effects on Lysosomal Alpha-Galactosidase: Potential Implications for the Cure of Fabry Disease

“…Our proposal for FD is even more promising when considering that combined therapeutic approaches for rare diseases have been proposed [ 100 , 101 , 102 , 103 , 104 ] and that most importantly, one of them was recently approved by the FDA for the treatment of cystic fibrosis [ 105 ].…”