Poly(ADP-ribose) synthase inhibition reduces ischemic injury and inflammation in neonatal rat brain.
Poly(ADP-ribose) synthase (PARS), an abundant nuclear protein, has been described as an important candidate for mediation of neurotoxicity by nitric oxide. However, in cerebral ischemia, excessive PARS activation may lead to energy depletion and exacerbation of neuronal damage. We examined the effect of inhibiting PARS on the (a) degree of cerebral injury, (b) process of inflammatory responses, and (c) functional outcomes in a neonatal rat model of focal ischemia. We demonstrate that administration of 3-aminobenzamide, a PARS inhibitor, leads to a significant reduction of infarct volume: 63 +/- 2 (untreated) versus 28 +/- 4 mm(3) (treated). The neuroprotective effects currently observed 48 h postischemia hold up at 7 and 17 days of survival time and attenuate neurological dysfunction. Inhibition of PARS activity, demonstrated by a reduction in poly(ADP-ribose) polymer formation, also reduces neutrophil recruitment and levels of nitrotyrosine, an indicator of peroxynitrite generation. Taken together, our results demonstrate that PARS inhibition reduces ischemic damage and local inflammation associated with reperfusion and may be of interest for the treatment of neonatal stroke.
Ducrocq
S
S
Université René Descartes-INSERM U. 29, Paris, France. Laboratoire de Pharmacologie de la Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Benjelloun
N
N
Plotkine
M
M
Ben-Ari
Y
Y
Charriaut-Marlangue
C
C
D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005260:Female; D008297:Male; D009043:Motor Activity; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology; D009566:Nitrates / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
D001549:Benzamides; D018696:Neuroprotective Agents; D009566:Nitrates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C025160:3-aminobenzamide