Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke.

Katalin Komjáti, John G. Mabley, László Virág, Garry J. Southan, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

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Abstract

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP). Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondria, but translocates to the nucleus, as shown by in vitro models of neuronal injury. Using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in a rat model of focal cerebral ischemia. The potency of INO-1001 as a PARP inhibitor and its cytoprotective potential in oxidant-challenged human neuronal SK-N-MC cells was first confirmed in vitro. PARP inhibition markedly reduced infarct size and improved neurological status in both transient and permanent models of MCA occlusion in Sprague-Dawley rats, with a therapeutic window of 6 h and 2 h in the transient and permanent ischemia models, respectively. The PARP inhibitor reduced the accumulation of poly(ADP-ribose) in the ischemic/reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunohistochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter. Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition is neuroprotective and regulates the ischemic nuclear translocation of AIF in stroke.

Original languageEnglish (US)
Pages (from-to)373-382
Number of pages10
JournalInternational Journal of Molecular Medicine
Volume13
Issue number3
StatePublished - Mar 2004
Externally publishedYes

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Apoptosis Inducing Factor
Poly(ADP-ribose) Polymerases
Stroke
Neurons
Brain Ischemia
Poly Adenosine Diphosphate Ribose
Flavoproteins
Nuclear Proteins
Oxidants
Sprague Dawley Rats
Axons
Mitochondria
Necrosis
Ischemia
White Matter
Staining and Labeling
Wounds and Injuries
INO 1001
Poly(ADP-ribose) Polymerase Inhibitors

ASJC Scopus subject areas

  • Genetics

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Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. / Komjáti, Katalin; Mabley, John G.; Virág, László; Southan, Garry J.; Salzman, Andrew L.; Szabo, Csaba.

In: International Journal of Molecular Medicine, Vol. 13, No. 3, 03.2004, p. 373-382.

Research output: Contribution to journalArticle

Komjáti, Katalin ; Mabley, John G. ; Virág, László ; Southan, Garry J. ; Salzman, Andrew L. ; Szabo, Csaba. / Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. In: International Journal of Molecular Medicine. 2004 ; Vol. 13, No. 3. pp. 373-382.
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