1. Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination.
- Author
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Chami M, Halmer R, Schnoeder L, Anne Becker K, Meier C, Fassbender K, Gulbins E, and Walter S
- Subjects
- Amyloid Precursor Protein Secretases genetics, Amyloid Precursor Protein Secretases metabolism, Animals, Astrocytes drug effects, Astrocytes enzymology, Astrocytes pathology, Axons drug effects, Axons enzymology, Axons pathology, Cell Count, Cuprizone, Demyelinating Diseases chemically induced, Demyelinating Diseases enzymology, Demyelinating Diseases pathology, Disease Models, Animal, Gene Expression Regulation, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia drug effects, Microglia enzymology, Microglia pathology, Multiple Sclerosis chemically induced, Multiple Sclerosis enzymology, Multiple Sclerosis pathology, Nerve Regeneration drug effects, Oligodendroglia enzymology, Oligodendroglia pathology, Recovery of Function drug effects, Sphingomyelin Phosphodiesterase antagonists & inhibitors, Sphingomyelin Phosphodiesterase deficiency, Synaptophysin genetics, Synaptophysin metabolism, Amitriptyline pharmacology, Demyelinating Diseases prevention & control, Enzyme Inhibitors pharmacology, Multiple Sclerosis prevention & control, Oligodendroglia drug effects, Sphingomyelin Phosphodiesterase genetics
- Abstract
The cuprizone animal model, also known as the toxic demyelination model, is a well-reproducible model of demyelination- and remyelination in mice, and has been useful in studying important aspect of human demyelinating diseases, including multiple sclerosis. In this study, we investigated the role of acid sphingomyelinase in demyelination and myelin repair by inducing acute and chronic demyelination with 5- or 12-week cuprizone treatment, followed by a 2-week cuprizone withdrawal phase to allow myelin repair. Sphingolipids, in particular ceramide and the enzyme acid sphingomyelinase, which generates ceramide from sphingomyelin, seem to be involved in astrocyte activation and neuronal damage in multiple sclerosis. We used immunohistochemistry to study glial reaction and oligodendrocyte distribution in acid sphingomyelinase deficient mice and wild-type C57BL/6J littermates at various time intervals after demyelination and remyelination. Axonal injury was quantified using amyloid precursor protein and synaptophysin, and gene expression and protein levels were measured using gene analysis and Western blotting, respectively. Our results show that mice lacking acid sphingomyelinase had a significant increase in myelin recovery and a significantly higher oligodendrocyte cell count after 2 weeks remyelination compared to wild-type littermates. Detrimental astroglial distribution was also significantly reduced in acid sphingomyelinase deficient animals. We obtained similar results in experiments using amitriptyline to inhibit acid sphingomyelinase. These findings suggest that acid sphingomyelinase plays a significant role in myelin repair, and its inhibition by amitriptyline may constitute a novel therapeutic approach for multiple sclerosis patients.
- Published
- 2017
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