engleski

Metallothionein I/II and megalin expressions in cuprizone model of multiple scerosis

Background: Metallothioneins (MTs) are small, cysteine-rich proteins, which have been implicated in variety of physiological and pathological processes, such as cell proliferation and apoptosis, detoxification of heavy metals and protection against oxidative stress and inflammation. Acting intracellularly, they regulate zinc and redox homeostasis and ensure proper functioning of metal-containing transcription factors, zinc-finger proteins and p53. Neuroprotective functions, however, might be mediated also by extracellular MTs, which signal through low-density lipoprotein family of receptors, such as lipoprotein receptor-1 and -2 (megalin). Design: In this study, we used a cuprizone-induced model of demyelination to examine the expression of MT-I+II, megalin and zinc and copper status in the brain of C57/BL6 mice at the time of massive oligodendrocyte degeneration and reactive astrogliosis (5 weeks after peroral cuprizone treatment). Results: The data have shown that MT proteins were diffusely upregulated in the white matter, as well as in the frontal cortex, hippocampus, subventricular zones and cerebellum. The majority of cells were astrocytes, but MTs were present also in some oligodendrocyte precursors. Upregulation of megalin expression was restricted to cerebral cortex. Surprisingly, qPCR analysis showed that enhanced MT protein expression was not followed by upregulation of MT-I mRNA, suggesting that progressive intoxication with cuprizone had downregulated the transcription of MT gene. The changes were associated with greater copper than zinc dyshomeostasis in the brain. Conclusion: Results show that MT I/II perform important cytoprotective and growth regulating functions in demyelination/remyelinating processes activated in the brain after toxic insults.

Metallothioneins I/II; cuprizone; demyelination.

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