Inhibition of poly(ADP)ribose polymerase protects against cuprizone-induced demyelination by preserving mitochondrial integrity in a degenerative murine model of multiple sclerosis
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1
Department of Biochemistry and Medical Chemistry, University of Pecs, Hungary
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2
Department of Neurology, University of Pecs, Hungary
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3
Department of Radiology, University of Pecs, Hungary
Multiple sclerosis (MS) is characterized by autoimmune inflammation and loss of myelin. In the earliest lesions and in pathological subtypes of III and IV, apoptosis-like depletion of oligodendrocytes but minor or absent inflammation have been described suggesting degenerative/toxic processes in the pathogenesis. Mitochondrial dysfunction, apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus and caspase-independent apoptosis have been indicated to play a role in the loss of oligodendrocytes and demyelination. In a primary demyelinating animal model of MS –induced by cuprizone–, the same morphological and molecular pathology was found. Moreover, activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), the MAP kinases and the PI3-kinase-Akt pathway was observed. Inhibition of PARP in this model attenuated oligodendrocyte death and decreased demyelination. PARP inhibition prevented caspase-independent AIF-mediated apoptosis, suppressed JNK and p38 MAP kinase phosphorylation and increased the activation of the cytoprotective PI3-kinase-Akt pathway. Our data show that PARP activation and the disturbed integrity of mitochondria play crucial role in the pathogenesis of cuprizone-induced lesions. PARP inhibition was previously reported to be effective in inflammatory models of MS, therefore PARP inhibitors may provide a therapy, which efficiently interferes with both demyelination and inflammation in MS.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Pathophysiology and neurology - degenerative disorders
Citation:
Veto
S,
Acs
P,
Berente
Z,
Doppler
H,
Kanizsai
A,
Lendvai
Z,
Komoly
S,
Illes
Z and
Gallyas
F
(2009). Inhibition of poly(ADP)ribose polymerase protects against cuprizone-induced demyelination by preserving mitochondrial integrity in a degenerative murine model of multiple sclerosis.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.180
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Received:
05 Mar 2009;
Published Online:
05 Mar 2009.
*
Correspondence:
Sara Veto, Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary, sara.veto@aok.pte.hu