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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

Renal biochemical and histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Serum creatinine levels (A) and representative renal sections (periodic acid-Schiff stained) (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05; n.s., not significant. Scale bar = 400 μm.
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f0015: Renal biochemical and histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Serum creatinine levels (A) and representative renal sections (periodic acid-Schiff stained) (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05; n.s., not significant. Scale bar = 400 μm.

Mentions: To evaluate renal toxicity, measurements of serum creatinine concentration and histological analysis were performed 8 h after subcutaneous administration of HPBCD (20,000 mg/kg) in Npc1 mutant mice. As shown in Fig. 3A, serum creatinine levels were significantly increased in the HPBCD-treated groups compared with the saline-treated groups of both Npc1+/+ and Npc1+/− mice. In contrast, little difference in the serum creatinine level was observed between the saline- and HPBCD-treated groups in Npc1−/− mice. Although urinary hemorrhage was observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups, no changes were observed in the HPBCD-treated Npc1−/− group. In histological analysis, significant vacuolization of the tubular epithelium and hyperplasia of the Bowman capsule were observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups (Fig. 3B). However, a slight degree of histological change induced by HPBCD was observed in the Npc1−/− mouse groups.


Influence of Npc1 genotype on the toxicity of hydroxypropyl- β -cyclodextrin, a potentially therapeutic agent, in Niemann – Pick Type C disease models ☆
Renal biochemical and histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Serum creatinine levels (A) and representative renal sections (periodic acid-Schiff stained) (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05; 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

f0015: Renal biochemical and histological analysis of wild-type and Npc1 mutant mice treated with a toxic dose of HPBCD.Serum creatinine levels (A) and representative renal sections (periodic acid-Schiff stained) (B) 8 h after saline or HPBCD (20,000 mg/kg) subcutaneous injection. Values are the mean ± S.E.M., (n = 5–7). * P < 0.05; n.s., not significant. Scale bar = 400 μm.
Mentions: To evaluate renal toxicity, measurements of serum creatinine concentration and histological analysis were performed 8 h after subcutaneous administration of HPBCD (20,000 mg/kg) in Npc1 mutant mice. As shown in Fig. 3A, serum creatinine levels were significantly increased in the HPBCD-treated groups compared with the saline-treated groups of both Npc1+/+ and Npc1+/− mice. In contrast, little difference in the serum creatinine level was observed between the saline- and HPBCD-treated groups in Npc1−/− mice. Although urinary hemorrhage was observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups, no changes were observed in the HPBCD-treated Npc1−/− group. In histological analysis, significant vacuolization of the tubular epithelium and hyperplasia of the Bowman capsule were observed in the HPBCD-treated Npc1+/+ and Npc1+/− mouse groups (Fig. 3B). However, a slight degree of histological change induced by HPBCD was observed in the Npc1−/− mouse groups.

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