Poly(adenosine diphosphate ribose) polymerase inhibition modulates spinal cord dysfunction after thoracoabdominal aortic ischemia-reperfusion

Patrick J. Casey, James H. Black, Csaba Szabo, Matthew Frosch, Hassan Albadawi, Min Chen, Richard P. Cambria, Michael T. Watkins

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 χ 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.

Original languageEnglish (US)
Pages (from-to)99-107
Number of pages9
JournalJournal of Vascular Surgery
Volume41
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Reperfusion
Spinal Cord
Ischemia
Paralysis
United Nations
Thorax
Adenosine Diphosphate Ribose
Spinal Cord Injuries
Nervous System Trauma
Nervous System
Staining and Labeling
Nervous System Malformations
Motor Neurons
Enzyme Inhibitors
Hematoxylin
Eosine Yellowish-(YS)
Neurologic Manifestations
Constriction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Poly(adenosine diphosphate ribose) polymerase inhibition modulates spinal cord dysfunction after thoracoabdominal aortic ischemia-reperfusion. / Casey, Patrick J.; Black, James H.; Szabo, Csaba; Frosch, Matthew; Albadawi, Hassan; Chen, Min; Cambria, Richard P.; Watkins, Michael T.

In: Journal of Vascular Surgery, Vol. 41, No. 1, 01.2005, p. 99-107.

Research output: Contribution to journalArticle

Casey, Patrick J. ; Black, James H. ; Szabo, Csaba ; Frosch, Matthew ; Albadawi, Hassan ; Chen, Min ; Cambria, Richard P. ; Watkins, Michael T. / Poly(adenosine diphosphate ribose) polymerase inhibition modulates spinal cord dysfunction after thoracoabdominal aortic ischemia-reperfusion. In: Journal of Vascular Surgery. 2005 ; Vol. 41, No. 1. pp. 99-107.
@article{02b9768bb77a4e34b4d8fdbc1f23c6d2,
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 χ 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.",
author = "Casey, {Patrick J.} and Black, {James H.} and Csaba Szabo and Matthew Frosch and Hassan Albadawi and Min Chen and Cambria, {Richard P.} and Watkins, {Michael T.}",
year = "2005",
month = "1",
doi = "10.1016/j.jvs.2004.10.040",
language = "English (US)",
volume = "41",
pages = "99--107",
journal = "Journal of Vascular Surgery",
issn = "0741-5214",
publisher = "Mosby Inc.",
number = "1",

}

TY - JOUR

T1 - Poly(adenosine diphosphate ribose) polymerase inhibition modulates spinal cord dysfunction after thoracoabdominal aortic ischemia-reperfusion

AU - Casey, Patrick J.

AU - Black, James H.

AU - Szabo, Csaba

AU - Frosch, Matthew

AU - Albadawi, Hassan

AU - Chen, Min

AU - Cambria, Richard P.

AU - Watkins, Michael T.

PY - 2005/1

Y1 - 2005/1

N2 - 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 χ 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.

AB - 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 χ 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.

UR - http://www.scopus.com/inward/record.url?scp=13244260793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13244260793&partnerID=8YFLogxK

U2 - 10.1016/j.jvs.2004.10.040

DO - 10.1016/j.jvs.2004.10.040

M3 - Article

C2 - 15696051

AN - SCOPUS:13244260793

VL - 41

SP - 99

EP - 107

JO - Journal of Vascular Surgery

JF - Journal of Vascular Surgery

SN - 0741-5214

IS - 1

ER -