Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice

M. Haddad, H. Rhinn, C. Bloquel, B. Coqueran, Csaba Szabo, M. Plotkine, D. Scherman, I. Margaill

Research output: Contribution to journalArticle

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Abstract

Background and purpose: Activation of poly(ADP-ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1). Experimental approach: Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25-25 mg kg -1) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis. Key results: Ischemia increased TNF-α protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-α at 6 h and 25 mg kg -1 PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg -1) reduced the increase in TNF-α mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL-6 (-41%), E-selectin (-81%) and ICAM-1 (-54%). PJ34 (25 mg kg -1) reduced the infarct volume (-26%) and improved neurological deficit, 24 h after ischemia. Conclusions and Implications: PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.

Original languageEnglish (US)
Pages (from-to)23-30
Number of pages8
JournalBritish Journal of Pharmacology
Volume149
Issue number1
DOIs
StatePublished - Sep 30 2006
Externally publishedYes

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Transient Ischemic Attack
Anti-Inflammatory Agents
Brain Ischemia
Ischemia
Tumor Necrosis Factor-alpha
E-Selectin
Poly(ADP-ribose) Polymerases
Intercellular Adhesion Molecule-1
Messenger RNA
Interleukin-6
Xylazine
Poly(ADP-ribose) Polymerase Inhibitors
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Middle Cerebral Artery Infarction
Ketamine
Real-Time Polymerase Chain Reaction
Cytokines

Keywords

  • Cerebral ischemia/reperfusion
  • PJ34
  • Poly (ADP-ribose) polymerase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice. / Haddad, M.; Rhinn, H.; Bloquel, C.; Coqueran, B.; Szabo, Csaba; Plotkine, M.; Scherman, D.; Margaill, I.

In: British Journal of Pharmacology, Vol. 149, No. 1, 30.09.2006, p. 23-30.

Research output: Contribution to journalArticle

Haddad, M. ; Rhinn, H. ; Bloquel, C. ; Coqueran, B. ; Szabo, Csaba ; Plotkine, M. ; Scherman, D. ; Margaill, I. / Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice. In: British Journal of Pharmacology. 2006 ; Vol. 149, No. 1. pp. 23-30.
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T1 - Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice

AU - Haddad, M.

AU - Rhinn, H.

AU - Bloquel, C.

AU - Coqueran, B.

AU - Szabo, Csaba

AU - Plotkine, M.

AU - Scherman, D.

AU - Margaill, I.

PY - 2006/9/30

Y1 - 2006/9/30

N2 - Background and purpose: Activation of poly(ADP-ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1). Experimental approach: Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25-25 mg kg -1) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis. Key results: Ischemia increased TNF-α protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-α at 6 h and 25 mg kg -1 PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg -1) reduced the increase in TNF-α mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL-6 (-41%), E-selectin (-81%) and ICAM-1 (-54%). PJ34 (25 mg kg -1) reduced the infarct volume (-26%) and improved neurological deficit, 24 h after ischemia. Conclusions and Implications: PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.

AB - Background and purpose: Activation of poly(ADP-ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1). Experimental approach: Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25-25 mg kg -1) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis. Key results: Ischemia increased TNF-α protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-α at 6 h and 25 mg kg -1 PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg -1) reduced the increase in TNF-α mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL-6 (-41%), E-selectin (-81%) and ICAM-1 (-54%). PJ34 (25 mg kg -1) reduced the infarct volume (-26%) and improved neurological deficit, 24 h after ischemia. Conclusions and Implications: PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.

KW - Cerebral ischemia/reperfusion

KW - PJ34

KW - Poly (ADP-ribose) polymerase

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