title: Poly(adenosine diphosphate ribose) polymerase inhibition modulates spinal cord dysfunction after thoracoabdominal aortic ischemia-reperfusion.
abstract: OBJECTIVE
  Spinal cord injury (SCI) remains a source of morbidity after thoracoabdominal aortic reconstruction. These studies were designed to determine whether PJ34, a novel ultrapotent inhibitor of the nuclear enzyme poly(adenosine diphosphate ribose) polymerase (PARP) could modulate neurologic injury after thoracic aortic ischemia reperfusion (TAR) in a murine model of SCI.
  
  
  METHODS
  Forty-one anesthetized male mice were subject to thoracic aortic occlusion (11 minutes) through a cervical mediastinotomy followed by 48 hours of reperfusion (TAR) under normothermic conditions. PJ34-treated mice (PJ, n = 12) were given 10 mg/kg PJ34 intraperitoneally 1 hour before ischemia and 1 hour after unclamping. The control group (UN, n = 21) received normal saline intraperitoneally 1 hour before ischemia and 1 hour after unclamping. Sham animals (n = 10) were subject to thoracic aortic exposure with no aortic clamping and similar intraperitoneal normal saline injections. PARP-1-/- (KO, n = 8) mice were subjected to the same conditions as the UN mice. Blinded observers rated murine neurologic status after TAR by using an established rodent paralysis scoring system. Murine spinal cords were subjected to cytokine (GRO-1) protein analysis as a marker of inflammation and immunohistochemical analysis (hematoxylin-eosin and PAR staining). Paralysis scores (PS) and GRO-1 levels were compared with analysis of variance, and survival data were compared with chi 2 .
  
  
  RESULTS
  Immediately after TAR, UN and PJ mice had severe neurologic dysfunction (PS = 5.8 +/- 0.1 and 4.6 +/- 0.6, respectively; P > .05), which was significantly worse than the KO mice (PS = 1.0 +/- 0.7, P < .001). After 6, 24, and 48 hours KO mice had no discernable neurologic injury (PS = 0). Six hours after TAR, PJ mice significantly improved (PS = 1.1 +/- 0.73, P < .001) and remained improved at 24 (PS = 0.7 +/- 0.6) and 48 hours (PS = 0.6 +/- 0.6). UN mice did not improve their PS, and Sham mice showed no neurologic abnormality at any time during these experiments. The mortality at 48 hours was 0% for PJ and KO mice, 43% for UN (P = .012), and 0% for Sham. GRO-1 levels were significantly decreased in PJ and KO versus UN mice (UN, 583 +/- 119 vs PJ, 5.8 +/- 0 vs KO, 5.3 +/- 1.4 mg/pg; P < .0001). Immunohistochemistry showed evidence of decreased PAR staining and ventral motor neuron injury in PJ mice.
  
  
  CONCLUSIONS
  Genetic deletion of PARP or inhibition of its activity (PJ34) rescued neurologic function in mice subjected to TAR. PARP inhibition might represent a novel therapeutic approach for prevention of SCI after TAR.
authors.affiliation: Division of Vascular-Endovascular Surgery, Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.forename: James H
authors.initials: JH
authors.lastname: Black
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: Matthew
authors.initials: M
authors.lastname: Frosch
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cambria
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal; D001013:Aorta, Thoracic; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015800:Protozoan Proteins; D015427:Reperfusion Injury / Q000517:prevention & control*; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013118:Spinal Cord Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C114254:PAR 1 protein, Trypanosoma cruzi; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015800:Protozoan Proteins; D011064:Poly Adenosine Diphosphate Ribose