Enhanced poly(ADP-ribosyl)ation after focal ischemia in rat brain.
Nitric oxide from neuronal cells plays detrimental roles in glutamate neurotoxicity and in focal brain ischemia. Nitric oxide directly damages DNA, and breaks in the DNA strands activate poly(ADP-ribose) polymerase (PARP), which brings poly(ADP-ribosyl)ation of the nuclear proteins. The excessive activation of PARP is thought to cause depletion of ATP and the energy failure resulting in cell death. To clarify the involvement of poly(ADP-ribosyl)ation in ischemic insult, we examined poly(ADP ribosyl)ation by immunohistochemical methods and the protective effect of 3-aminobenzamide, which is a PARP inhibitor, on focal brain ischemia using an intraluminal permanent middle cerebral artery occlusion model in rats. Poly(ADP ribosyl)ation was widely and markedly detected 2 hours after the ischemic insult in the cerebral cortex and striatum in which infarction developed 24 hours later. The enhanced immunoreactivity of poly(ADP-ribose) gradually decreased, and 16 hours later, no immunoreactivity was detected. Intraventricular administration of 3-aminobenzamide (1 to 30 mg/kg) 30 minutes before the ischemic insult decreased infarction volume in a dose-dependent manner along with the immunohistochemical reduction of poly(ADP-ribosyl)ation. Pretreatment with 7-nitroindazole (25 mg/kg, intraperitoneally), a selective neuronal nitric oxide synthetase inhibitor, partially reduced poly(ADP-ribosyl)ation. These data suggest the involvement of poly(ADP-ribosyl)ation in the development of cerebral infarction.
Tokime
T
T
Department of Neurosurgery, Faculty of Medicine, Kyoto University, Japan.
Nozaki
K
K
Sugino
T
T
Kikuchi
H
H
Hashimoto
N
N
Ueda
K
K
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole