Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
ACS Appl Bio Mater. 2022 May 16;5(5):2377-2388. doi: 10.1021/acsabm.2c00233. Epub 2022 May 4.
Niemann-Pick disease type C (NPC) is characterized by the accumulation of glycolipids such as free cholesterol, sphingomyelin, and gangliosides in late endosomes/lysosomes (endolysosomes) due to abnormalities in the membrane proteins NPC1 or NPC2. The main symptoms of NPC caused by free cholesterol accumulation in various tissues vary depending on the time of onset, but hepatosplenomegaly and neurological symptoms accompanied by decreased motor, cognitive, and mental functions are observed in all age groups. However, the efficacy of NPC treatment remains limited. Herein, we have fabricated lactose-appended hydroxypropyl-β-cyclodextrin (Lac-HPβCD) and evaluated its lowering effects on cholesterol accumulation in NPC model mice. We reveal that Lac-HPβCD lowers cholesterol accumulation in the liver and spleen by reducing the amount of free cholesterol. Moreover, Lac-HPβCD reduces the amount of free cholesterol in the cerebrum and slightly alleviates motor dysfunction. These results suggest that Lac-HPβCD has potential for the treatment of NPC.
尼曼-匹克病 C 型（NPC）的特征是由于 NPC1 或 NPC2 膜蛋白异常，导致晚期内体/溶酶体（内溶酶体）中游离胆固醇、神经鞘磷脂和神经节苷脂等糖脂积累。由于各种组织中游离胆固醇积累引起的 NPC 的主要症状因发病时间而异，但在所有年龄组中均观察到肝脾肿大和伴有运动、认知和精神功能下降的神经症状。然而，NPC 的治疗效果仍然有限。在此，我们制备了乳糖修饰的羟丙基-β-环糊精（Lac-HPβCD），并评估了其降低 NPC 模型小鼠胆固醇积累的效果。我们揭示了 Lac-HPβCD 通过减少游离胆固醇的量来降低肝脏和脾脏中的胆固醇积累。此外，Lac-HPβCD 减少了大脑中的游离胆固醇含量，并轻微改善了运动功能障碍。这些结果表明 Lac-HPβCD 具有治疗 NPC 的潜力。
