Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death
Autor: | György Sétáló, Gábor Borgulya, Balazs Sumegi, Sámuel Komoly, Ferenc Gallyas, Sara Veto, Jan Bauer, Zoltán Berente, Péter Ács, Zsolt Illes, Hans Lassmann |
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Rok vydání: | 2010 |
Předmět: |
Male
Programmed cell death Multiple Sclerosis Poly ADP ribose polymerase Active Transport Cell Nucleus Apoptosis Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor Article chemistry.chemical_compound Cuprizone Mice medicine Animals Protein kinase B Polymerase Myelin Sheath Cell Nucleus biology Cell Death Adenosine diphosphate ribose Apoptosis Inducing Factor Brain Oligodendrocyte Mice Inbred C57BL Disease Models Animal Oligodendroglia medicine.anatomical_structure chemistry Immunology biology.protein Cancer research Apoptosis-inducing factor Neurology (clinical) Poly(ADP-ribose) Polymerases Demyelinating Diseases Signal Transduction |
Zdroj: | Brain : a journal of neurology. 133(Pt 3) |
ISSN: | 1460-2156 |
Popis: | Oligodendrocyte loss and demyelination are major pathological hallmarks of multiple sclerosis. In pattern III lesions, inflammation is minor in the early stages, and oligodendrocyte apoptosis prevails, which appears to be mediated at least in part through mitochondrial injury. Here, we demonstrate poly(ADP-ribose) polymerase activation and apoptosis inducing factor nuclear translocation within apoptotic oligodendrocytes in such multiple sclerosis lesions. The same morphological and molecular pathology was observed in an experimental model of primary demyelination, induced by the mitochondrial toxin cuprizone. Inhibition of poly(ADP-ribose) polymerase in this model attenuated oligodendrocyte depletion and decreased demyelination. Poly(ADP-ribose) polymerase inhibition suppressed c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation, increased the activation of the cytoprotective phosphatidylinositol-3 kinase-Akt pathway and prevented caspase-independent apoptosis inducing factor-mediated apoptosis. Our data indicate that poly(ADP-ribose) polymerase activation plays a crucial role in the pathogenesis of pattern III multiple sclerosis lesions. Since poly(ADP-ribose) polymerase inhibition was also effective in the inflammatory model of multiple sclerosis, it may target all subtypes of multiple sclerosis, either by preventing oligodendrocyte death or attenuating inflammation. |
Databáze: | OpenAIRE |
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