Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice

Marianne Haddad, Virginie Beray-Berthat, Bérard Coqueran, Bruno Palmier, Csaba Szabo, Michel Plotkine, Isabelle Margaill

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Hemorrhagic transformation is an aggravating event that occurs in 15 to 43% of patients suffering from ischemic stroke. This phenomenon due to blood-brain barrier breakdown appears to be mediated in part by matrix metalloproteinases (MMPs) among which MMP-2 and MMP-9 could be particularly involved. Recent experimental studies demonstrated that post-ischemic MMP-9 overexpression is regulated by poly(ADP-ribose)polymerase (PARP). In this context, our study aimed to evaluate the effect of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetamide), a potent PARP inhibitor, on MMP-2 and MMP-9 levels and on hemorrhagic transformations in a model of permanent focal cerebral ischemia in mice. PJ34 (6.25-12.5 mg/kg, i.p.) was given at the time of ischemia onset and 4 h later. Hemorrhagic transformations, divided into microscopic and macroscopic hemorrhages, were counted 48 h after ischemia on 12 coronal brain slices. Microscopic and macroscopic hemorrhages were respectively reduced by 38% and 69% with 6.25 mg/kg PJ34. The anti-hemorrhagic effect of PJ34 was associated with a 57% decrease in MMP-9 overexpression assessed by gelatin zymography. No increase in MMP-2 activity was observed after ischemia in our model. The vascular protection achieved by PJ34 was associated with a reduction in the motor deficit (P < 0.05) and in infarct volume (- 31%, P < 0.01). In conclusion, our study demonstrates for the first time that PJ34 reduces hemorrhagic transformations after cerebral ischemia. Thus this PARP inhibitor exhibits both anti-hemorrhagic and neuroprotective effects that may be of valuable interest for the treatment of stroke.

Original languageEnglish (US)
Pages (from-to)52-57
Number of pages6
JournalEuropean Journal of Pharmacology
Volume588
Issue number1
DOIs
StatePublished - Jun 24 2008
Externally publishedYes

Fingerprint

Brain Ischemia
Matrix Metalloproteinase 9
Matrix Metalloproteinase 2
Ischemia
Stroke
Hemorrhage
Poly(ADP-ribose) Polymerases
Neuroprotective Agents
Gelatin
Blood-Brain Barrier
Matrix Metalloproteinases
Blood Vessels
Poly(ADP-ribose) Polymerase Inhibitors
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Brain

Keywords

  • Cerebral hemorrhage
  • Matrix metalloproteinase
  • PARP (poly(ADP-ribose)polymerase)
  • PJ34
  • Stroke

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice. / Haddad, Marianne; Beray-Berthat, Virginie; Coqueran, Bérard; Palmier, Bruno; Szabo, Csaba; Plotkine, Michel; Margaill, Isabelle.

In: European Journal of Pharmacology, Vol. 588, No. 1, 24.06.2008, p. 52-57.

Research output: Contribution to journalArticle

Haddad, Marianne ; Beray-Berthat, Virginie ; Coqueran, Bérard ; Palmier, Bruno ; Szabo, Csaba ; Plotkine, Michel ; Margaill, Isabelle. / Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice. In: European Journal of Pharmacology. 2008 ; Vol. 588, No. 1. pp. 52-57.
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abstract = "Hemorrhagic transformation is an aggravating event that occurs in 15 to 43{\%} of patients suffering from ischemic stroke. This phenomenon due to blood-brain barrier breakdown appears to be mediated in part by matrix metalloproteinases (MMPs) among which MMP-2 and MMP-9 could be particularly involved. Recent experimental studies demonstrated that post-ischemic MMP-9 overexpression is regulated by poly(ADP-ribose)polymerase (PARP). In this context, our study aimed to evaluate the effect of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetamide), a potent PARP inhibitor, on MMP-2 and MMP-9 levels and on hemorrhagic transformations in a model of permanent focal cerebral ischemia in mice. PJ34 (6.25-12.5 mg/kg, i.p.) was given at the time of ischemia onset and 4 h later. Hemorrhagic transformations, divided into microscopic and macroscopic hemorrhages, were counted 48 h after ischemia on 12 coronal brain slices. Microscopic and macroscopic hemorrhages were respectively reduced by 38{\%} and 69{\%} with 6.25 mg/kg PJ34. The anti-hemorrhagic effect of PJ34 was associated with a 57{\%} decrease in MMP-9 overexpression assessed by gelatin zymography. No increase in MMP-2 activity was observed after ischemia in our model. The vascular protection achieved by PJ34 was associated with a reduction in the motor deficit (P < 0.05) and in infarct volume (- 31{\%}, P < 0.01). In conclusion, our study demonstrates for the first time that PJ34 reduces hemorrhagic transformations after cerebral ischemia. Thus this PARP inhibitor exhibits both anti-hemorrhagic and neuroprotective effects that may be of valuable interest for the treatment of stroke.",
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AU - Coqueran, Bérard

AU - Palmier, Bruno

AU - Szabo, Csaba

AU - Plotkine, Michel

AU - Margaill, Isabelle

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