Abstract | OBJECTIVES:
Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1(-/-) mouse by combining three therapies that each targets unique aspects of the pathogenic cascade. METHODS: RESULTS/INTERPRETATION: We have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1(-/-) mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease.
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Authors | Ian M Williams, Kerri-Lee Wallom, David A Smith, Nada Al Eisa, Claire Smith, Frances M Platt |
Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 67
Pg. 9-17
(Jul 2014)
ISSN: 1095-953X [Electronic] United States |
PMID | 24631719
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 Elsevier Inc. All rights reserved. |
Chemical References |
- Intracellular Signaling Peptides and Proteins
- Neuroprotective Agents
- Niemann-Pick C1 Protein
- Npc1 protein, mouse
- Proteins
- 1-Deoxynojirimycin
- miglustat
- Curcumin
- Ibuprofen
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Topics |
- 1-Deoxynojirimycin
(analogs & derivatives, therapeutic use)
- Animals
- Cerebellum
(drug effects, pathology)
- Curcumin
(therapeutic use)
- Drug Therapy, Combination
- Ibuprofen
(therapeutic use)
- Intracellular Signaling Peptides and Proteins
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Neuroprotective Agents
(therapeutic use)
- Niemann-Pick C1 Protein
- Niemann-Pick Disease, Type C
(drug therapy)
- Proteins
(genetics)
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