Inhibition of Poly(ADP-Ribose) Polymerase Attenuates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits

Abstract

Background and Purpose-Poly(ADP-ribose) polymerase (PARP) is important in modulating inflammation, which has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the role of PARP in vasospasm using 3-aminobenzamide (3-AB), a PARP inhibitor, in a rabbit model. Methods-Twenty-four New Zealand White rabbits were divided into 4 groups: (1) no treatment (control group, nϭ6); (2) blood injection without pretreatment (SAH-only group, nϭ6); (3) blood injection with pretreatment by vehicle (SAHϩvehicle group, nϭ6); and (4) blood injection with pretreatment by 3-AB (SAHϩ3-AB group, nϭ6). We used the single-hemorrhage model of SAH, injecting autologous arterial blood into the cisterna magna. Angiography was performed before (baseline) and after (day 2) SAH, and the diameter of the basilar artery (BA) was measured. Animals were euthanatized after the second angiogram. After perfusion and fixation, the brains were cut into sections for hematoxylin and eosin and immunohistochemical staining for poly(ADP-ribosyl)ation. Results-In the control group, there were no differences in the BA lumen caliber between baseline and day 2 (96.8Ϯ10.4%). Cerebral vasospasm in the SAHϩ3-AB group (88.2Ϯ6.2%) was remarkably attenuated in comparison with that in the SAH-only group (64.9Ϯ8.0%) and the SAHϩvehicle group (65.6Ϯ10.8%). The BA in the SAHϩ3-AB group showed less corrugation of the tunica elastica interna than that in the SAH-only and SAHϩvehicle groups. Staining for poly(ADP-ribosyl)ation was markedly inhibited in smooth muscle and adventitial cells of the BA in the SAHϩ3-AB group compared with other groups. Key Words: nitric oxide synthase Ⅲ subarachnoid hemorrhage Ⅲ vasospasm Ⅲ rabbits F ree radicals, such as peroxynitrite and hydroxyl radical, trigger the breakage of single strands of DNA and subsequently activate the nuclear enzyme poly(ADP-ribose) polymerase (PARP). When PARP is activated, nicotinamide adenine dinucleotide is dissipated, and its regeneration requires adenosine triphosphate. Therefore, PARP activation leads to cell death through energy depletion. 1-3 Inhibiting PARP has reduced ischemic 4-6 and traumatic 7 brain injury in experimental animal models. Szabó et al 8 -11 have demonstrated that PARP may also modulate the course of inflammation by regulating the expression of adhesion molecules, neutrophil infiltration, nuclear factor-B (NF-B), and inducible nitric oxide synthase (iNOS), all of which are responsible for inflammation. Recent experimental data show that PARP activation is associated with the pathogenesis of a variety of inflammatory diseases, such as arthritis 12,13 and meningitis. 14 Conclusions-Inhibiting See Editorial Comment, page 231Cerebral vasospasm is an important cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Although the pathogenesis of vasospasm is not fully understood, an inflammatory response has been suggested to be involved. [15][16][17] Oxyhemoglobin in hemolysate within a subarachnoid clot is considered one of the candidates respo...

Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage

“…Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that regulates adhesion molecule expression and neutrophil recruitment during inflammation [107]. In a rabbit model of SAH, Satoh and colleagues showed PARP activation within the smooth muscle and adventitia of blood-exposed vessels and that PARP inhibition decreased the severity of vasospasm [108]. …”

Inflammation following stroke

“…77 Interestingly, various anti-inflammatory strategies reduced the vasospasm after SAH in these animals. [78][79][80] Hence, controlling inflammation after haemorrhagic stroke also seems to have beneficial effects similar to those in ischaemic stroke.…”

Poly (ADP-Ribose) Polymerase Inhibitors as Potential Therapeutic Agents in Stroke and Neurotrauma

“…[110,[113][114][115]. Similarly, additional Newborn piglet E.coli meningitis 3-AB Decrease in lactate production, neutrophil infiltration, TNFα production, peroxidation and ATP depletion [161] Mice, rats E.coli meningitis 3-AB, PARP -/-phenotype Decrease in inflammatory mediator production, improved survival and CNS function [162] Rabbit SAH 3-AB Attenuated vasospasm [163] Abbreviations no (ADP-ribose) formation is observed in PARP -/-tissue [63] and NAD + levels were spared [121]. PARP activation is mainly related to NO production by the neuronal isoform of NOS, because in mice deficient in this enzyme, when subjected to middle cerebral artery occlusion/reperfusion, PARP activation was found to be markedly diminished [120].…”