日本語フィールド
著者：*Yusei Yamada, Toru Miwa, Masaki Nakashima, Aina Shirakawa, Akira Ishii, Nanami Namba, Yuki Kondo, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki, Yasuyo Okada, Atsushi Ichikawa, Katsumi Higaki, Ken Hayashi, Kentaro Minami, Naoki Yoshikawa, Ryuji Ikeda, Yoshihide Ishikawa, Tomohito Kajii, Kyoko Tachii, Hiroki Takeda, Yorihisa Orita, Muneaki Matsuo, Tetsumi Irie, Yoichi Ishitsuka題名：Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann-Pick disease type C without hearing loss発表情報：Biomed Pharmacother 巻: 155 ページ: 113698キーワード：Cholesterol; Cyclodextrin; Niemann?Pick disease type C; Ototoxicity; Physicochemical property; Solubilization概要：Niemann-Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application. 抄録：英語フィールド
Author：*Yusei Yamada, Toru Miwa, Masaki Nakashima, Aina Shirakawa, Akira Ishii, Nanami Namba, Yuki Kondo, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki, Yasuyo Okada, Atsushi Ichikawa, Katsumi Higaki, Ken Hayashi, Kentaro Minami, Naoki Yoshikawa, Ryuji Ikeda, Yoshihide Ishikawa, Tomohito Kajii, Kyoko Tachii, Hiroki Takeda, Yorihisa Orita, Muneaki Matsuo, Tetsumi Irie, Yoichi IshitsukaTitle：Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann-Pick disease type C without hearing lossAnnouncement information:Biomed Pharmacother Vol: 155 Page: 113698Keyword：Cholesterol; Cyclodextrin; Niemann?Pick disease type C; Ototoxicity; Physicochemical property; SolubilizationAn abstract：Niemann-Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application. 