The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals.
Poly(ADP-ribose) polymerase (PARP) plays an important role in ischaemic cell death, and 3-aminobenzamide (3-AB), one of the PARP inhibitors, has a protective effect on ischaemic stroke. We investigated the neuroprotective mechanisms of 3-AB in ischaemic stroke. The occlusion of middle cerebral artery (MCA) was made in 170 Sprague-Dawley rats, and reperfusion was performed 2 h after the occlusion. Another 10 Sprague-Dawley rats were used for sham operation. 3-AB was administered to 85 rats 10 min before the occlusion [3-AB group (n = 85) vs. control group without 3-AB (n = 85)]. Infarct volume and water content were measured, brain magnetic resonance imaging, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labelling (TUNEL) and Cresyl violet staining were performed, and immunoreactivities (IRs) of poly(ADP-ribose) polymer (PAR), cleaved caspase-3, CD11b, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), phospho-Akt (pAkt) and phospho-glycogen synthase kinase-3 (pGSK-3) were compared in the peri-infarcted region of the 3-AB group and its corresponding ischaemic region of the control group at 2, 8, 24 and 72 h after the occlusion. In the 3-AB group, the infarct volume and the water content were decreased (about 45% and 3.6%, respectively, at 24 h), the number of TUNEL-positive cells was decreased (about 36% at 24 h), and the IRs of PAR, cleaved caspase-3, CD11b, ICAM-1 and COX-2 were significantly reduced, while the IRs of pAkt and pGSK-3 were increased. These results suggest that 3-AB treatment could reduce the infarct volume by reducing ischaemic cell death, its related inflammation and increasing survival signals. The inhibition of PARP could be another potential neuroprotective strategy in ischaemic stroke.
Koh
Seong-Ho
SH
Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
Park
Younjoo
Y
Song
Chi Won
CW
Kim
Jun Gyou
JG
Kim
Kisok
K
Kim
Juhan
J
Kim
Myung-Ho
MH
Lee
Seung Ro
SR
Kim
Dong Won
DW
Yu
Hyun-Jeung
HJ
Chang
Dae-Il
DI
Hwang
Se Jin
SJ
Kim
Seung Hyun
SH
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2; D011464:Epoprostenol / Q000031:analogs & derivatives*; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013997:Time Factors
D001549:Benzamides; D039481:CD11b Antigen; D007527:Isoenzymes; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011518:Proto-Oncogene Proteins; C068518:TTC 909; D018799:Intercellular Adhesion Molecule-1; C025160:3-aminobenzamide; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases