日本語フィールド
著者：*Yusei Yamada, Yoichi Ishitsuka, Yuki Kondo, Shuichi Nakahara, Asami Nishiyama, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Shunsuke Kamei, Tsuyoshi Shuto, Hirofumi Kai, Yuji Hayashino, Masatake Sugita, Takeshi Kikuchi, Fumio Hirata, Toru Miwa, Hiroki Takeda, Yorihisa Orita, Takahiro Seki, Tomoko Ohta, Yuki Kurauchi, Hiroshi Katsuki, Muneaki Matsuo, Katsumi Higaki, Kousaku Ohno, Shirou Matsumoto, Takumi Era, Tetsumi Irie題名：Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C 発表情報：Br J Pharmacol 巻: 178 号: 13 ページ: 2727-2746キーワード：Niemann-Pick disease type C; cholesterol; cyclodextrin; lipid trafficking; lysosomal storage disease; molecular dynamics概要：Background and purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear.
Experimental approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.
Key results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC.
Conclusions and implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity.抄録：英語フィールド
Author：*Yusei Yamada, Yoichi Ishitsuka, Yuki Kondo, Shuichi Nakahara, Asami Nishiyama, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Shunsuke Kamei, Tsuyoshi Shuto, Hirofumi Kai, Yuji Hayashino, Masatake Sugita, Takeshi Kikuchi, Fumio Hirata, Toru Miwa, Hiroki Takeda, Yorihisa Orita, Takahiro Seki, Tomoko Ohta, Yuki Kurauchi, Hiroshi Katsuki, Muneaki Matsuo, Katsumi Higaki, Kousaku Ohno, Shirou Matsumoto, Takumi Era, Tetsumi IrieTitle：Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C Announcement information:Br J Pharmacol Vol: 178 Issue: 13 Page: 2727-2746Keyword：Niemann-Pick disease type C; cholesterol; cyclodextrin; lipid trafficking; lysosomal storage disease; molecular dynamicsAn abstract：Background and purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear.
Experimental approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.
Key results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC.
Conclusions and implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity.