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


METHODS
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.


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
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.
Haddad
M
M
Paris Descartes University, Faculty of Pharmacy, UPRES EA2510, Pharmacologie de la Circulation Cérébrale, Paris, France.
Rhinn
H
H
Bloquel
C
C
Coqueran
B
B
Szabó
C
C
Plotkine
M
M
Scherman
D
D
Margaill
I
I
D000818:Animals; D000893:Anti-Inflammatory Agents; D001921:Brain / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002544:Cerebral Infarction / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D002546:Ischemic Attack, Transient / Q000473:pathology*; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D004791:Enzyme Inhibitors; D015850:Interleukin-6; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1