Journal Article

Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination

Halmer, Ramona, Walter, Silke, Chami, Marwan, Gulbins, Erich, Anne Becker, Katrin, Meier, Carola, Schnoeder, Laura, Fassbender, Klaus

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Activation / Activation analysis / Alzheimer's disease / Amitriptyline / Amitriptyline - pharmacology / Amyloid beta-protein / Amyloid precursor protein / Amyloid Precursor Protein Secretases - genetics / Amyloid Precursor Protein Secretases - metabolism / Analysis / Animal experimentation / Animal models / Animals / Apoptosis / Astrocytes - drug effects / Astrocytes - enzymology / Astrocytes - pathology / Autoimmune diseases / Axons - drug effects / Axons - enzymology / Axons - pathology / Biology and Life Sciences / Brain / Cell Count / Ceramide / Cuprizone / Damage / Demyelinating diseases / Demyelinating Diseases - chemically induced / Demyelinating Diseases - enzymology / Demyelinating Diseases - pathology / Demyelinating Diseases - prevention & control / Demyelination / Disease Models, Animal / Diseases / Enzyme Inhibitors - pharmacology / Fibroblasts / Gene expression / Gene Expression Regulation / Growth factors / Humans / Immunohistochemistry / Inhibition / Injuries / Laboratories / Male / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Microglia - drug effects / Microglia - enzymology / Microglia - pathology / Molecular biology / Multiple sclerosis / Multiple Sclerosis - chemically induced / Multiple Sclerosis - enzymology / Multiple Sclerosis - pathology / Multiple Sclerosis - prevention & control / Myelin / Myelination / Nerve Regeneration - drug effects / Neurology / Neuronal-glial interactions / Neurosciences / Oligodendroglia - drug effects / Oligodendroglia - enzymology / Oligodendroglia - pathology / Patients / Proteins / Recovery / Recovery of Function - drug effects / Regulation / Repair / Research and Analysis Methods / Rodents / Sphingolipids / Sphingomyelin / Sphingomyelin phosphodiesterase / Sphingomyelin Phosphodiesterase - antagonists & inhibitors / Sphingomyelin Phosphodiesterase - deficiency / Sphingomyelin Phosphodiesterase - genetics / Studies / Synaptophysin / Synaptophysin - genetics / Synaptophysin - metabolism / Western blotting