Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Hoque, Sanzana; Kondo, Yuki; Sakata, Nodoka; Yamada, Yoshiki; Fukaura, Madoka; Higashi, Taishi; Motoyama, Keiichi; Arima, Hisatomi; Higaki, Kazutaka; Hayashi, Akio; Komiya, Takaki; Ishitsuka, Yoichi; Irie, Tetsumi

doi:10.3390/ijms21030898

Cited by 18 publications

(11 citation statements)

References 46 publications

(56 reference statements)

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“…However, whether cholesterol is the true target molecule of HP-β-CD in the attenuation of NPC disease conditions has remained controversial, and Davidson et al [ 5 ] suggested that HP-β-CD may interact with other NPC disease-related substrates, such as sphingolipids. Indeed, we previously demonstrated that HP-β-CD can significantly attenuate sphingomyelin accumulation in Npc1 -deficient Chinese hamster ovarian cells, as well as the accumulation of free cholesterol [ 24 ]. Marques et al [ 25 ] reported that glucocerebrosidase 2 gene knockout and pharmacological inhibition ameliorated the manifestations of NPC, such as Purkinje cell loss, motor dysfunction, and shortened lifespan, without correcting cholesterol levels, in Npc1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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

Fukaura

Ishitsuka

Shirakawa

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

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

Fukaura

Ishitsuka

Shirakawa

et al. 2021

IJMS

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“…The existing literature data demonstrate that the γCD derivative HPγCD may act as a therapeutic approach for Niemann-Pick type C disease (NPC) [ 84 , 85 , 86 , 87 , 88 ], which is a fatal neurodegenerative disorder characterized by a massive accumulation of free cholesterol and other lipids in late endosomes and lysosomes. In addition, NPC1-deficient cells showed defects in autophagy [ 89 , 90 ].…”

Section: Application Of Cyclodextrinsmentioning

confidence: 99%

“…However, the underlying mechanism of action remains to be clarified. Hoque et al [ 88 ] showed that both HPβCD and HPγCD (but not HPαCD) reduced cholesterol and sphingolipid accumulation solely in Npc1-null Chinese hamster ovary cells, but not in the corresponding control wild-type cells.…”

Section: Application Of Cyclodextrinsmentioning

confidence: 99%

Cyclodextrins, Natural Compounds, and Plant Bioactives—A Nutritional Perspective

2021

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Cyclodextrins (CDs) are a group of cyclic oligosaccharides produced from starch or starch derivatives. They contain six (αCD), seven (βCD), eight (γCD), or more glucopyranose monomers linked via α-1,4-glycosidic bonds. CDs have a truncated cone shape with a hydrophilic outer wall and a less hydrophilic inner wall, the latter forming a more apolar internal cavity. Because of this special architecture, CDs are soluble in water and can simultaneously host lipophilic guest molecules. The major advantage of inclusion into CDs is increased aqueous solubility of such lipophilic substances. Accordingly, we present studies where the complexation of natural compounds such as propolis and dietary plant bioactives (e.g., tocotrienol, pentacyclic triterpenoids, curcumin) with γCD resulted in improved stability, bioavailability, and bioactivity in various laboratory model organisms and in humans. We also address safety aspects that may arise from increased bioavailability of plant extracts or natural compounds owing to CD complexation. When orally administered, α- and βCD—which are inert to intestinal digestion—are fermented by the human intestinal flora, while γCD is almost completely degraded to glucose units by α-amylase. Hence, recent reports indicate that empty γCD supplementation exhibits metabolic activity on its own, which may provide opportunities for new applications.

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“…HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced the level of sphingomyelins in Npc1 -null, but not wild-type, cells. 2-hydroxypropyl-γ-cyclodextrin appears to have therapeutic potential, but more research is needed (Hoque et al 2020 ).…”

Section: Hp-β-cdmentioning

confidence: 99%

Treatment trials in Niemann-Pick type C disease

2021

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Niemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood–brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

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Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Cited by 18 publications

References 46 publications

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

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

Cyclodextrins, Natural Compounds, and Plant Bioactives—A Nutritional Perspective

Treatment trials in Niemann-Pick type C disease

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