engleski

Expression profile of metallothionein I+II and megalin in cuprizone model of demyelination

Abstract Copper chelator cuprizone (bis-cyclohexanone-oxalyldihydrazone, CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent oligodendrocyte apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. Owing to well known anti-oxidative, growth-regulating and neuroprotectve properties of metallothioneins (MTs), in this study we analyzed the expression profile of MT-I+II and its receptor megalin (low-density lipoprotein receptor related protein-2) in the brain of mice subjected to different protocols of CPZ feeding. Experiments were performed in female C57BL/6 mice fed with 0.25 % cuprizone during 1, 3 and 5 weeks. They were sacrificed immediately after feeding with CPZ or 2 weeks after the withdrawal of CPZ. The data, obtained by immunohistochemistry and immunofluorescence showed that CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and its receptor in the white matter (corpus callosum and internal capsule), as well as in the grey matter of the brain (cortex, hippocampus, cerebellum). Moreover, in numerous cortical neurons and some progenitor cells the signs of MT endocytosis was found supporting the hypothesis that MTs secreted from the astrocytes might directly affect the neuronal differentiation and survival. Furthermore, in mice treated with CPZ for 5 weeks the prominent MTs and megalin immunoreactivities were found on several neural stem cells and oligodendrocyte progenitors (GFAP+, nestin+, doublecortin+ and NG2+ cells) located in subgranular zone of dentate gyrus and subventricular zone of lateral ventricules, pointing to high modulatory effect of MTs on adult neurogenesis. The data show that MT I/II perform important cytoprotective and growth regulating functions in reparatory/remyelinating processes activated in the brain after toxic demyelinating insults.

cuprizone, demyelination, megalin, metallothionein I+II

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