Expression Profiles of Metallothionein I/II and Megalin in Cuprizone Model of De- and Remyelination

Abstract

Copper chelator cuprizone (CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. To explore the participation of metallothioneins (MTs) in these processes, in this study we analyzed the expression profiles of MT-I/II and their 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% CPZ during 1, 3 and 5 weeks. They were sacrificed immediately after feeding with CPZ or 2 weeks after the withdrawal of CPZ. The data showed that CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and megalin in white (corpus callosum and internal capsule) and gray matter of the brain (cortex, hippocampus, and cerebellum). Moreover, in numerous cortical neurons and progenitor cells the signs of MT/megalin interactions and Akt1 phosphorylation 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 in subgranular zone of dentate gyrus and subventricular zone of lateral ventricles pointing to high modulatory effect of MTs on adult neuro- and oligodendrogenesis. The data show that MT I/II perform important cytoprotective and growth-regulating functions in remyelinating processes activated after toxic demyelinating insults.

Metallothioneins and Megalin Expression Profiling in Premalignant and Malignant Oral Squamous Epithelial Lesions

“…More recently, several studies indicated that extracellular MTs can bind to multiligand scavenger receptor megalin, also known as low-density lipoprotein receptor-related protein-2 (LRP-2) and gp330 [ 23 , 24 ]. It is thought that resulting membrane complex MT-megalin could either trigger pro-survival and pro-mitotic pathways via protein kinase B (PKB, AKT-1) activation through SH2/SH3 domains or/and undergo endocytic internalization regulated by NPXY sequences, thereby supplying the cell with “exogenous” MTs, that may be even directly shuttled into the nucleus upon endocytosis [ 25 , 26 , 27 , 28 , 29 ]. Apart from that, upon ligand binding, megalin can be, as with Notch, subjected to regulated intramembrane proteolysis (RIP) resulting in cleavage and release of C-terminal soluble megalin intracellular domain (LRP-2-ICD; MICD), which consequently enters the cell nucleus where directly modifies gene expression [ 30 , 31 , 32 ].…”

Effects of Androgen Receptor Inhibition on Kanamycin-Induced Hearing Loss in Rats

“…In addition to antioxidant effects, MTs are considered reactive proteins that possess neuroprotective and regenerative effects [ 20 ]. In a mouse model of cuprizone-induced neurotoxicity, the expression levels of MT1/MT2 and megalin were increased in certain brain regions [ 21 ]. Thus, the increased expression of megalin and MT1A and MT2A ligands can induce oxidative and inflammatory responses in KM rats; in the present study, this was reversed in KM + FM rats by blocking the signaling cascades of the androgen receptor, megalin, and MT1A.…”

Arecoline attenuates memory impairment and demyelination in a cuprizone-induced mouse model of schizophrenia

“…Copper chelator CPZ is neurotoxicant, which selectively disrupts the respiratory chain of oligodendrocyte, leading to oxidative stress and subsequent apoptosis 17. CPZ-treated animals are well-accepted demyelination models that could induce schizophrenia-like behaviors including memory impairment, and thus, it can be used to induce mouse demyelination model of schizophrenia 8,14,16.…”