Back to Search
Start Over
Iron chelation by deferiprone does not rescue the Niemann-Pick Disease Type C1 mouse model
- Source :
- BioMetals. 33:87-95
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Niemann-Pick Disease Type C (NP-C) is a fatal lysosomal storage disorder with progressive neurodegeneration. In addition to the characteristic cholesterol and lipid overload phenotype, we previously found that altered metal homeostasis is also a pathological feature. Increased brain iron in the Npc1-/- mouse model of NP-C may potentially contribute to neurodegeneration, similar to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Deferiprone (DFP) is a brain penetrating iron chelator that has demonstrated effectiveness in preventing neurological deterioration in Parkinson's disease clinical trials. Therefore, we hypothesized that DFP treatment, targeting brain iron overload, may have therapeutic benefits for NP-C. Npc1-/- mice were assigned to four experimental groups: (1) pre-symptomatic (P15) + 75 mg/kg DFP; (2) pre-symptomatic (P15) + 150 mg/kg DFP; (3) symptomatic (P49) + 75 mg/kg DFP; (4) symptomatic (P49) + 150 mg/kg DFP. Our study found that in Npc1-/- mice, DFP treatment did not offer any improvement over the expected disease trajectory and median lifespan. Moreover, earlier treatment and higher dose of DFP resulted in adverse effects on body weight and onset of ataxia. The outcome of our study indicated that, despite increased brain iron, Npc1-/- mice were vulnerable to pharmacological iron depletion, especially in early life. Therefore, based on the current model, iron chelation therapy is not a suitable treatment option for NP-C.
- Subjects :
- Male
Ataxia
Pharmacology
Iron Chelating Agents
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Biomaterials
Mice
03 medical and health sciences
chemistry.chemical_compound
Niemann-Pick C1 Protein
medicine
Animals
Deferiprone
Adverse effect
030304 developmental biology
Mice, Knockout
Mice, Inbred BALB C
0303 health sciences
Niemann–Pick disease, type C
Cholesterol
business.industry
030302 biochemistry & molecular biology
Neurodegeneration
Intracellular Signaling Peptides and Proteins
Metals and Alloys
medicine.disease
Disease Models, Animal
chemistry
Female
medicine.symptom
NPC1
General Agricultural and Biological Sciences
business
Injections, Intraperitoneal
Oxidative stress
Subjects
Details
- ISSN :
- 15728773 and 09660844
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- BioMetals
- Accession number :
- edsair.doi.dedup.....9c7b898bfe6319f14d6cda6f3369e727