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Influence of Npc1 genotype on the toxicity of hydroxypropyl- β -cyclodextrin, a potentially therapeutic agent, in Niemann – Pick Type C disease models ☆

View Article: PubMed Central - PubMed

ABSTRACT

Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) or Npc1+/− mice died by 72 h after the injection. In contrast, all of the Npc1−/− mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1+/+ or Npc1+/− mice. However, these pathophysiological changes were significantly alleviated in Npc1−/− mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1−/− mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1+/+ or Npc1+/− mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

No MeSH data available.


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Pulmonary histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Representative lung sections (hematoxylin eosin stained) (A) and lung injury scores (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Lung injury score was measured as described in the Material and Methods. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05, ** P < 0.01; n.s., not significant. Scale bar = 400 μm.
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f0020: Pulmonary histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Representative lung sections (hematoxylin eosin stained) (A) and lung injury scores (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Lung injury score was measured as described in the Material and Methods. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05, ** P < 0.01; n.s., not significant. Scale bar = 400 μm.

Mentions: Lung histological sections of the saline-treated Npc1+/+ and Npc1+/− mouse groups exhibited normal morphology. In contrast, severe hemorrhage, infiltration of inflammatory cells, and thickened alveolar septum were observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups (Fig. 4A). Many vacuolated alveolar macrophages were found in both the saline- and HPBCD-treated Npc1−/− mouse groups. Minor lung pathological changes that were exhibited in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups were also observed in the HPBCD-treated Npc1−/− mouse group. As shown in Fig. 4B, the histopathological scores in the HPBCD-treated groups were significantly higher than in the saline-treated Npc1+/+ and Npc1+/− mouse groups. In contrast, significant differences were not observed between the HPBCD- and saline-treated groups of Npc1−/− mice.


Influence of Npc1 genotype on the toxicity of hydroxypropyl- β -cyclodextrin, a potentially therapeutic agent, in Niemann – Pick Type C disease models ☆
Pulmonary histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Representative lung sections (hematoxylin eosin stained) (A) and lung injury scores (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Lung injury score was measured as described in the Material and Methods. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05, ** P < 0.01; n.s., not significant. Scale bar = 400 μm.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121301&req=5

f0020: Pulmonary histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Representative lung sections (hematoxylin eosin stained) (A) and lung injury scores (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Lung injury score was measured as described in the Material and Methods. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05, ** P < 0.01; n.s., not significant. Scale bar = 400 μm.
Mentions: Lung histological sections of the saline-treated Npc1+/+ and Npc1+/− mouse groups exhibited normal morphology. In contrast, severe hemorrhage, infiltration of inflammatory cells, and thickened alveolar septum were observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups (Fig. 4A). Many vacuolated alveolar macrophages were found in both the saline- and HPBCD-treated Npc1−/− mouse groups. Minor lung pathological changes that were exhibited in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups were also observed in the HPBCD-treated Npc1−/− mouse group. As shown in Fig. 4B, the histopathological scores in the HPBCD-treated groups were significantly higher than in the saline-treated Npc1+/+ and Npc1+/− mouse groups. In contrast, significant differences were not observed between the HPBCD- and saline-treated groups of Npc1−/− mice.

View Article: PubMed Central - PubMed

ABSTRACT

Hydroxypropyl-&beta;-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann&ndash;Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000&nbsp;mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) or Npc1+/&minus; mice died by 72&nbsp;h after the injection. In contrast, all of the Npc1&minus;/&minus; mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1+/+ or Npc1+/&minus; mice. However, these pathophysiological changes were significantly alleviated in Npc1&minus;/&minus; mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1&minus;/&minus; mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1+/+ or Npc1+/&minus; mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

No MeSH data available.


Related in: MedlinePlus