Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann–Pick Disease Type C Model Mice

• Main Authors: Madoka Fukaura, Yoichi Ishitsuka, Seiichi Shirakawa, Naoki Ushihama, Yusei Yamada, Yuki Kondo, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki, Katsumi Higaki, Muneaki Matsuo, Tetsumi Irie
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: Niemann–Pick disease type C; 2-hydroxypropyl-β-cyclodextrin; glycoprotein nonmetastatic melanoma B
• Online Access: https://www.mdpi.com/1422-0067/22/1/452
• ISSN: 1661-6596; 1422-0067

Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the <i>NPC1</i> or <i>NPC2</i> gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-β-CD in <i>Npc1</i> gene-deficient (<i>Npc1</i>^−/−) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in <i>Npc1</i>^−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in <i>Npc1</i>^−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of <i>Npc1</i>^−/− mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment.