Document Detail

Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life.
MedLine Citation:
PMID:  20581737     Owner:  NLM     Status:  MEDLINE    
Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 mouse, s.c. with β-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease.
Charina M Ramirez; Benny Liu; Anna M Taylor; Joyce J Repa; Dennis K Burns; Arthur G Weinberg; Stephen D Turley; John M Dietschy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pediatric research     Volume:  68     ISSN:  1530-0447     ISO Abbreviation:  Pediatr. Res.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-16     Completed Date:  2011-01-11     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0100714     Medline TA:  Pediatr Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  309-15     Citation Subset:  IM    
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MeSH Terms
Anticholesteremic Agents / administration & dosage*
Biological Transport
Brain / drug effects,  metabolism
Cholesterol / metabolism*
Disease Models, Animal
Drug Administration Schedule
Injections, Subcutaneous
Liver / drug effects,  metabolism
Liver Diseases / metabolism,  pathology,  prevention & control
Lung / drug effects,  metabolism
Lung Diseases / metabolism,  pathology
Macrophages / drug effects,  metabolism
Mice, Inbred BALB C
Mice, Mutant Strains
Nerve Degeneration / metabolism,  pathology,  prevention & control
Niemann-Pick Disease, Type C / drug therapy*,  genetics,  metabolism,  pathology
Proteins / genetics*
Time Factors
beta-Cyclodextrins / administration & dosage*
Grant Support
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Npc1 protein, mouse; 0/Proteins; 0/beta-Cyclodextrins; 94035-02-6/2-hydroxypropyl-beta-cyclodextrin; 97C5T2UQ7J/Cholesterol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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