Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death.
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.
Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, Pecs, 12 Szigeti St, Hungary.
Sara
S
Veto
Peter
P
Acs
Jan
J
Bauer
Hans
H
Lassmann
Zoltan
Z
Berente
Gyorgy
G
Setalo
Gabor
G
Borgulya
Balazs
B
Sumegi
Samuel
S
Komoly
Ferenc
F
Gallyas
Zsolt
Z
Illes
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology / Q000502:physiology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009186:Myelin Sheath / Q000201:enzymology / Q000502:physiology; D009836:Oligodendroglia / Q000201:enzymology* / Q000502:physiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction
D051033:Apoptosis Inducing Factor; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003471:Cuprizone; D011065:Poly(ADP-ribose) Polymerases