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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.


Related in: MedlinePlus

Effect of HPBCD injection on survival rate of Npc1 mutant mice.Npc1+/+ (n = 12), Npc1+/− (n = 12) and Npc1−/− (n = 11) mice were administered HPBCD (20,000 mg/kg) subcutaneously and monitored for 72 h.
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f0005: Effect of HPBCD injection on survival rate of Npc1 mutant mice.Npc1+/+ (n = 12), Npc1+/− (n = 12) and Npc1−/− (n = 11) mice were administered HPBCD (20,000 mg/kg) subcutaneously and monitored for 72 h.

Mentions: We examined the effects of subcutaneously injected 20,000 mg/kg of HPBCD on survival in Npc1 mutant mice. Over half of the mice of the Npc1+/+ or Npc1+/− groups were dead within 72 h by an administration of HPBCD (Fig. 1). Stress responses, such as anorexia and fluffing and withering of the fur, were observed in the surviving mice of the wild-type and Npc1+/− groups. In contrast, all of the Npc1−/− mice survived, and stress responses exhibited by the Npc1+/− mice were not observed. In the Kaplan–Meier analysis, significant differences were observed in the Npc1−/− group compared with the Npc1+/+ and Npc1+/− groups. Although statistical significances were not observed between the Npc1+/+ and Npc1+/− groups, the survival of the Npc1+/+ group tended to be lower than that of the Npc1+/− groups (p = 0.108 in log-rank test).


Influence of Npc1 genotype on the toxicity of hydroxypropyl- β -cyclodextrin, a potentially therapeutic agent, in Niemann – Pick Type C disease models ☆
Effect of HPBCD injection on survival rate of Npc1 mutant mice.Npc1+/+ (n = 12), Npc1+/− (n = 12) and Npc1−/− (n = 11) mice were administered HPBCD (20,000 mg/kg) subcutaneously and monitored for 72 h.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: Effect of HPBCD injection on survival rate of Npc1 mutant mice.Npc1+/+ (n = 12), Npc1+/− (n = 12) and Npc1−/− (n = 11) mice were administered HPBCD (20,000 mg/kg) subcutaneously and monitored for 72 h.
Mentions: We examined the effects of subcutaneously injected 20,000 mg/kg of HPBCD on survival in Npc1 mutant mice. Over half of the mice of the Npc1+/+ or Npc1+/− groups were dead within 72 h by an administration of HPBCD (Fig. 1). Stress responses, such as anorexia and fluffing and withering of the fur, were observed in the surviving mice of the wild-type and Npc1+/− groups. In contrast, all of the Npc1−/− mice survived, and stress responses exhibited by the Npc1+/− mice were not observed. In the Kaplan–Meier analysis, significant differences were observed in the Npc1−/− group compared with the Npc1+/+ and Npc1+/− groups. Although statistical significances were not observed between the Npc1+/+ and Npc1+/− groups, the survival of the Npc1+/+ group tended to be lower than that of the Npc1+/− groups (p = 0.108 in log-rank test).

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.


Related in: MedlinePlus