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PMID: 19750228 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

PloS one ·Vol. 4 ·No. 9 ·2009-09-11 ·Pages e6951

Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU

Abstract

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

MeSH Terms
1-Deoxynojirimycin/administration & dosage,analogs & derivatives 2-Hydroxypropyl-beta-cyclodextrin Animals Cholesterol/metabolism Cyclodextrins/administration & dosage Disease Models, Animal Disease Progression Drug Synergism Enzyme Inhibitors/therapeutic use Glycosphingolipids/metabolism Mice Mice, Transgenic Neurons/metabolism Niemann-Pick Disease, Type C/drug therapy Pregnanolone/administration & dosage Treatment Outcome beta-Cyclodextrins/administration & dosage
Chemicals
Cyclodextrins Enzyme Inhibitors Glycosphingolipids beta-Cyclodextrins 1-Deoxynojirimycin 2-Hydroxypropyl-beta-cyclodextrin Cholesterol miglustat Pregnanolone
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Davidson Cristin D
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Ali Nafeeza F
Micsenyi Matthew C
Stephney Gloria
Renault Sophie
Dobrenis Kostantin
Ory Daniel S
Vanier Marie T
Walkley Steven U
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0006951
Published
2009-09-11
Epub
2009-00-11
Pages
e6951
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2736622
Subset
IM
Grants
NICHD NIH HHS · R01 HD045561 · United States
NICHD NIH HHS · HD045561 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0006951 PMC Full Text View journal details
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