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Clinical Neuroscience

JULY 30, 2012

[Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination]

ÁCS Péter, KOMOLY Sámuel

[Background and purpose - It has been reported that multiple sclerosis has four different neuropathological subtypes, and two of them (type III and IV) are characterized by primary oligodendrocyte loss. However, the exact pathomechanism that lead to oligodendrocyte apoptosis in human demyelinating diseases is still elusive. The copper chelator cuprizone induces primary oligodendrocyte apoptosis and consequent demyelination in well defined areas of the mouse brain. Nevertheless, the precise subcellular events that result in oligodendrocyte cell death in the cuprizone model are still unknown. We aimed to study the ultrastructural alterations that might induce oligodendrocyte apoptosis in the cuprizone experimental demyelination model. Methods - C57BL/6 mice were given cuprizone for two, 21 and 35 days to induce demyelination to investigate early pathological events, and different stages of demyelination. In addition, mice were given cuprizone for 35 days and were allowed to recover for two or 14 days to study early and late remyelination. After the cuprizone treatment, mice were sacrificed and the corpus callosum, the superior cerebellar peduncle, the optic nerve and the sciatic nerve were studied by electron microscopy. Results - The ultrastructural analysis revealed that cuprizone induced oligodendrocyte apoptosis is accompanied by the formation of giant mitochondria in the affected cells in the corpus callosum and in the superior cerebellar peduncle. Apoptosis of the myelin producing cells was present through the whole cuprizone challenge. Severe demyelination occurred after three weeks of cuprizone administration associated with massive macrophage infiltration and astrocytosis of the demyelinated areas. Axons and neurons remained unaffected. Conclusion - The formation of giant mitochondria in myelin producing oligodendrocytes is the first pathological sign in the cuprizone experimental demyelination. Mitochondrium pathology in the cuprizone challenge might serve as a useful model to study the pathomechanism of multiple sclerosis subtypes (III and IV) characterized by primary oligodendrocyte degeneration.]

Clinical Neuroscience

JANUARY 20, 2005

[EXPERIMENTAL DEMYELINATION CAUSED BY PRIMARY OLIGODENDROCYTE DYSTROPHY Regional distribution of the lesions in the nervous system of mice brain]

KOMOLY Sámuel

[Background and purpose - Heterogeneity of multiple sclerosis lesions has been recently indicated: In addition to T-cell-mediated or T-cell plus antibody-mediated autoimmune mechanisms (patterns I-II) two other patterns (III-IV) were described. Patterns III-IV are characterized by primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. It was described more than 30 years ago that dietary application of a copper-chelating agent called cuprizone results in primary oligodendrocyte degeneration which is followed by demyelination. The aim of the present study was to examine the regional distribution of cuprizone induced oligodendrocyte dystrophy and demyelination in the nervous system of mice. Material a methods - Demyelination was induced in male weanling Swis-Webster mice by feeding them on a diet containing 0.6% (W/W) cuprizone bis(cyclohexanone)-oxalyldihydrazone (G. F. Smith Chemical, Columbus OH) for 8 weeks. Animals were sacrificed after 3, 7, 14, 27, 35, 56 days of cuprizone administration. Samples were taken from corpus callosum, anterior commissure, optic nerve, cervical spinal cord and sciatic nerve. Samples were examined by immunohistochemistry, in situ hybridization for myelin proteins and myelin protein mRNA-s, respectively. Conventional neuropathological stainings and electron microscopy was also performed. Results - Oligodendrocyte degeneration and demyelination followed a particular standard pattern in the central nervous system. Profound myelin loss developed in the superior cerebellar peduncle, anterior comissure and corpus callosum, whereas the optic nerves, velum medullare anterior and spinal cord showed little or no demyelination. Sciatic nerves were unaffected. No infiltration by lymphocytes or blood-brain barrier damage was observed during cuprizone treatment. Conclusion - Cuprizone induced oligodendrocyte damage and demyelination follows a particular standard pattern in the central nervous system of mice. Cuprizone induced demyelination might be considered as a model for human demyelinating disorders with primary oligodendrocyte dystrophy and apoptosis.]