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.

Abstract

Niemann-Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 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 Npc1 gene-deficient (Npc1-/-) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1-/- 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 Npc1-/- 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 Npc1-/- 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.

• 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 1 (Jan 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33466390 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Eye Proteins
• Glycoproteins
• Gpnmb protein, mouse
• Membrane Glycoproteins
• 2-Hydroxypropyl-beta-cyclodextrin
• Cholesterol

Topics

• 2-Hydroxypropyl-beta-cyclodextrin (administration & dosage)
• Animals
• Biomarkers (metabolism)
• Cerebellum (drug effects, metabolism)
• Cholesterol (metabolism)
• Disease Models, Animal
• Eye Proteins (metabolism)
• Female
• Glycoproteins (metabolism)
• Infusions, Intraventricular
• Liver (drug effects, metabolism)
• Male
• Melanoma (metabolism)
• Membrane Glycoproteins (metabolism)
• Mice
• Neurons (drug effects, metabolism)
• Niemann-Pick Disease, Type C (drug therapy, metabolism)
• Purkinje Cells (drug effects, metabolism)