The strong pathology of NPC1-/- mice, a Niemann-Pick type 1 mouse model, can be significantly reduced by cyclodextrin treatment. Here we show that cyclodextrin (2-hydroxypropyl-ß-cyclodextrin, HPBCD improves cholesterol levels as well as liver enzyme levels. Subcutaneous treatment of NPC1-/- mice once weekly for 3 weeks thus reduces liver cholesterol levels (Fig.1A) while increasing plasma triglyceride levels (Fig. 1C). Plasma cholesterol, HDL, and LDL levels increase in NPC1-/- mice, but cyclodextrin treatment does not significantly reverse these pathologies (Fig.1B, D, E).
Figure 1: Effect of cyclodextrin treatment on cholesterol, triglycerides, HDL and LDL. NPC1-/- and wild type animals (n = 6 per group) were analyzed for cholesterol in the liver (A), cholesterol (B), triglycerides (C), HDL (D) and LDL (E) in the plasma after 3 weeks of treatment with cyclodextrin (Cyclo) or vehicle. One-way ANOVA followed by Dunn’s multiple comparison post hoc test; mean + SEM; *p<0.05; **p<0.01; ***p<0.001.
Evaluation of liver enzymes shows strongly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) levels in NPC1-/- mice (Fig.2). Cyclodextrin treatment markedly reverses AST and ALT levels back to wild type levels (Fig.2A, B), while ALP levels are unaffected by cyclodextrin (Fig.2C).
Figure 2: Effect of cyclodextrin treatment on liver enzymes. NPC1-/- and wild type animals (n = 6 per group) were analyzed for aspartate aminotransferase (AST, A), alanine aminotransferase (ALT, B), and alkaline phosphatase (ALP, C) levels in the plasma. Kruskal-Wallis test followed by Dunn’s multiple comparison post hoc test (AST and ALT) or One-way ANOVA followed by Dunnett’s multiple comparison test (ALP); mean + SEM; ***p<0.001.
Cyclodextrin is therefore a valuable reference compound to evaluate new compounds for their in vivo efficacy against this lysosomal storage disease. As cyclodextrin is currently already tested for the use in NPC1-deficient patients, results of preclinical studies using cyclodextrin as reference compound will have a highly translational significance.
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