The effects of a combination of ion channel inhibitors on pathology in a model of demyelinating disease
| Autor: | Alexander Gough, Melinda Fitzgerald, Andrew Warnock, Gopana Gopalasingam, Carole A. Bartlett, Terence McGonigle, Abbey Ford, Maimuna Majimbi, Lillian M. Toomey |
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| Rok vydání: | 2018 |
| Předmět: |
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DNA damage Cations Divalent Ion Channels Corpus Callosum OLIG2 03 medical and health sciences Myelin Cuprizone Random Allocation 0302 clinical medicine medicine Demyelinating disease Animals 030212 general & internal medicine Node of Ranvier Lomerizine biology business.industry General Medicine medicine.disease Myelin basic protein Cell biology Mice Inbred C57BL Disease Models Animal Oxidative Stress medicine.anatomical_structure Neuroprotective Agents nervous system Neurology biology.protein Calcium Drug Therapy Combination Neurology (clinical) business Neuroglia 030217 neurology & neurosurgery Astrocyte medicine.drug Demyelinating Diseases |
| Zdroj: | Multiple sclerosis and related disorders. 34 |
| ISSN: | 2211-0356 |
| Popis: | Background Multiple sclerosis (MS) has been shown to feature oxidative damage, which can be modelled using the cuprizone model of demyelinating disease. Oxidative damage can occur as a result of excessive influx of calcium ions (Ca2+) and oligodendroglia are particularly vulnerable. However, the effects of limiting excess Ca2+ influx on oxidative damage, oligodendroglia and myelin structure are unknown. Objective This study investigated the effects of limiting excess Ca2+ flux on oxidative damage and associated changes in oligodendroglial densities and Node of Ranvier structure in the cuprizone model. Methods The effects of three weeks of cuprizone administration and of treatment with a combination of three ion channel inhibitors (Lomerizine, Brilliant Blue G (BBG) and YM872), were semi-quantified immunohistochemically. Outcomes assessed were protein nitration (3-nitrotyrosine (3NT)) oxidative damage to DNA (8-hydroxy deoxyguanosine (8OHDG)), advanced glycation end-products (carboxymethyl lysine (CML)), immunoreactivity of microglia (Iba1) and astrocytes (glial acidic fibrillary protein (GFAP)), densities of oligodendrocyte precursor cells (OPCs) (platelet derived growth factor alpha receptor (PDGFαR) with olig2) and oligodendrocytes (olig2 and CC1), and structural elements of the Node of Ranvier (contactin associated protein (Caspr)). Results The administration of cuprizone resulted in increased protein nitration, DNA damage, and astrocyte and microglial immunoreactivity, a decrease in the density of oligodendrocytes and OPCs, together with altered structure of the Node of Ranvier and reduced myelin basic protein immunoreactivity. Treatment with the ion channel inhibitor combination significantly lowered protein nitration, increased the density of OPCs and reduced the number of atypical Node of Ranvier complexes; other outcomes were unaffected. Conclusion Our findings suggest that excess Ca2+ influx contributes to protein nitration, and associated changes to OPC densities and Node of Ranvier structure in demyelinating disease. |
| Databáze: | OpenAIRE |
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