Distribution of Poly(ADP-ribosyl)ation and cell death after cerebral ischemia in the neonatal rat.
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is a key component of molecular mechanisms leading to cell death or survival after an ischemic insult. Oxidative stress damages DNA, and breaks in the DNA strands activate PARP enzyme, leading to poly(ADP-ribosyl)ation of nuclear proteins. In this study, we investigated PARP activation using immunodetection of PAR polymers in the brain of neonatal rat pups subjected to unilateral focal ischemia with reperfusion. PARP activation was detected in the ischemic core between 2 and 18 h, and in the penumbra between 24 and 48 h in the middle cerebral artery (MCA) territory but also in territories of the anterior and posterior cerebral artery, and in white matter tracts. The intranuclear accumulation of PAR in cells preceded a positive terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling, suggesting that PARP activation may actually contribute to delayed cell death. Pretreatment with 3-aminobenzamide (3-AB, 10 mg/kg) strongly reduced PARP activation and cell death. These data suggest that PARP activation represents, in the immature brain, the early sign of ischemic cell death. This raises the possibility of the use of PARP inhibitors not only immediately postischemia but perhaps also later to reduce ischemic lesion in the MCA territory and its connected structures.
Joly
Luc-Marie
LM
UPRES EA 2510, Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Benjelloun
Nabila
N
Plotkine
Michel
M
Charriaut-Marlangue
Christiane
C
D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases