Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice.
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.
Haddad
Marianne
M
Equipe de recherche "Pharmacologie de la Circulation Cérébrale" (EA 2510), Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Beray-Berthat
Virginie
V
Coqueran
Bérard
B
Palmier
Bruno
B
Szabo
Csaba
C
Plotkine
Michel
M
Margaill
Isabelle
I
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000523:psychology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002544:Cerebral Infarction / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011597:Psychomotor Performance / Q000187:drug effects
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D045726:Metalloproteases