Inhibiting poly(ADP-ribose) polymerase

A potential therapy against oligodendrocyte death

Sara Veto, Peter Acs, Jan Bauer, Hans Lassmann, Z. Berente, Gyorgy Setalo, Gabor Borgulya, B. Sümegi, S. Komoly, F. Gallyas, Zsolt Illes

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)822-834
Number of pages13
JournalBrain
Volume133
Issue number3
DOIs
Publication statusPublished - Mar 2010

Fingerprint

Poly(ADP-ribose) Polymerases
Oligodendroglia
Multiple Sclerosis
Demyelinating Diseases
Apoptosis Inducing Factor
Cuprizone
Phosphatidylinositol 3-Kinase
Apoptosis
Inflammation
Therapeutics
Molecular Pathology
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Caspases
Theoretical Models
Phosphorylation
Wounds and Injuries

Keywords

  • AIF
  • Akt
  • Cuprizone
  • Demyelination
  • JNK
  • Multiple sclerosis
  • Oligodendrocyte apoptosis
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Veto, S., Acs, P., Bauer, J., Lassmann, H., Berente, Z., Setalo, G., ... Illes, Z. (2010). Inhibiting poly(ADP-ribose) polymerase: A potential therapy against oligodendrocyte death. Brain, 133(3), 822-834. https://doi.org/10.1093/brain/awp337

Inhibiting poly(ADP-ribose) polymerase : A potential therapy against oligodendrocyte death. / Veto, Sara; Acs, Peter; Bauer, Jan; Lassmann, Hans; Berente, Z.; Setalo, Gyorgy; Borgulya, Gabor; Sümegi, B.; Komoly, S.; Gallyas, F.; Illes, Zsolt.

In: Brain, Vol. 133, No. 3, 03.2010, p. 822-834.

Research output: Contribution to journalArticle

Veto, Sara ; Acs, Peter ; Bauer, Jan ; Lassmann, Hans ; Berente, Z. ; Setalo, Gyorgy ; Borgulya, Gabor ; Sümegi, B. ; Komoly, S. ; Gallyas, F. ; Illes, Zsolt. / Inhibiting poly(ADP-ribose) polymerase : A potential therapy against oligodendrocyte death. In: Brain. 2010 ; Vol. 133, No. 3. pp. 822-834.
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