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

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-alpha (TNF-alpha) 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-alpha protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-alpha 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-alpha 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.

• Authors: M Haddad, H Rhinn, C Bloquel, B Coqueran, C Szabó, M Plotkine, D Scherman, I Margaill
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 1 Pg. 23-30 (Sep 2006) ISSN: 0007-1188 [Print] England
• PMID: 16865091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cell Adhesion Molecules
• Cytokines
• E-Selectin
• Enzyme Inhibitors
• Interleukin-6
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Anti-Inflammatory Agents
• Brain (pathology)
• Cell Adhesion Molecules (biosynthesis)
• Cerebral Infarction (pathology)
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• E-Selectin (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Intercellular Adhesion Molecule-1 (biosynthesis)
• Interleukin-6 (biosynthesis)
• Ischemic Attack, Transient (pathology)
• Male
• Mice
• Nervous System Diseases (chemically induced, physiopathology)
• Phenanthrenes (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Messenger (biosynthesis)
• Tumor Necrosis Factor-alpha (biosynthesis)