Local Administration of the Poly ADP-Ribose Polymerase (PARP) Inhibitor, PJ34 During Hindlimb Ischemia Modulates Skeletal Muscle Reperfusion Injury

Mark F. Conrad, Hassan Albadawi, David H. Stone, Robert S. Crawford, Fateh Entabi, Michael T. Watkins

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: PARP stabilizes DNA and modulates inflammation in murine models of sepsis, stroke, and myocardial infarction. Previous studies have shown that systemic PARP inhibition before hindlimb ischemia preserves tissue viability and modulates cytokine synthesis during reperfusion. The purpose of this study was to determine whether intra-muscular (IM) administration of PJ34, a potent inhibitor of PARP, after the onset of acute hindlimb ischemia (post hoc) modulates the local production of inflammatory mediators during ischemia/reperfusion (I/R). Materials and methods: The control tension tourniquet was used to establish unilateral hindlimb ischemia in mice for 3 h followed by 48 h I/R. The treatment group (PJ) received IM PJ34 (10 mg/kg) in the affected hindlimb 90 min into ischemia whereas the control group (UN) received IM saline (150 uL) at the same time point. Skeletal muscle viability (MTT mitochondrial activity), local neutrophil chemoattractant protein (KC), Interleukin 6 (IL-6), Interleukin 1β (IL-1β), and Myeloperoxidase (MPO) levels were measured in protein extracts after the reperfusion period. Results: Muscle viability (102% ± 10 PJ, 78% ± 4 UN, P = 0.04), IL-B (21.1 ± 1.3 PJ, 15.5 ± 1.0 UN, P = 0.02), and IL-6 levels (16.3 ± 1.2 PJ, 10.9 ± 1.4 UN, P = 0.04) after 48 I/R were significantly higher in PJ. KC and MPO levels were higher in PJ but neither reached statistical significance. Conclusions: Post hoc PJ34 therapy appears to protect skeletal muscle from I/R injury despite increased levels of local cytokines. These initial findings support the role of local post hoc therapy in the treatment of acute limb threatening ischemia suggesting that further study of this novel therapy is warranted.

Original languageEnglish (US)
Pages (from-to)233-237
Number of pages5
JournalJournal of Surgical Research
Volume135
Issue number2
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

Fingerprint

Hindlimb
Reperfusion Injury
Skeletal Muscle
Ischemia
United Nations
Reperfusion
Poly(ADP-ribose) Polymerases
Peroxidase
Interleukin-6
Cytokines
Tissue Survival
Tourniquets
Chemotactic Factors
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Poly(ADP-ribose) Polymerase Inhibitors
Interleukin-1
Sepsis
Proteins
Neutrophils
Therapeutics

Keywords

  • cytokines
  • hindlimb
  • ischemia
  • murine
  • myeloperoxidase
  • PJ34
  • reperfusion

ASJC Scopus subject areas

  • Surgery

Cite this

Local Administration of the Poly ADP-Ribose Polymerase (PARP) Inhibitor, PJ34 During Hindlimb Ischemia Modulates Skeletal Muscle Reperfusion Injury. / Conrad, Mark F.; Albadawi, Hassan; Stone, David H.; Crawford, Robert S.; Entabi, Fateh; Watkins, Michael T.

In: Journal of Surgical Research, Vol. 135, No. 2, 01.10.2006, p. 233-237.

Research output: Contribution to journalArticle

Conrad, Mark F. ; Albadawi, Hassan ; Stone, David H. ; Crawford, Robert S. ; Entabi, Fateh ; Watkins, Michael T. / Local Administration of the Poly ADP-Ribose Polymerase (PARP) Inhibitor, PJ34 During Hindlimb Ischemia Modulates Skeletal Muscle Reperfusion Injury. In: Journal of Surgical Research. 2006 ; Vol. 135, No. 2. pp. 233-237.
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abstract = "Background: PARP stabilizes DNA and modulates inflammation in murine models of sepsis, stroke, and myocardial infarction. Previous studies have shown that systemic PARP inhibition before hindlimb ischemia preserves tissue viability and modulates cytokine synthesis during reperfusion. The purpose of this study was to determine whether intra-muscular (IM) administration of PJ34, a potent inhibitor of PARP, after the onset of acute hindlimb ischemia (post hoc) modulates the local production of inflammatory mediators during ischemia/reperfusion (I/R). Materials and methods: The control tension tourniquet was used to establish unilateral hindlimb ischemia in mice for 3 h followed by 48 h I/R. The treatment group (PJ) received IM PJ34 (10 mg/kg) in the affected hindlimb 90 min into ischemia whereas the control group (UN) received IM saline (150 uL) at the same time point. Skeletal muscle viability (MTT mitochondrial activity), local neutrophil chemoattractant protein (KC), Interleukin 6 (IL-6), Interleukin 1β (IL-1β), and Myeloperoxidase (MPO) levels were measured in protein extracts after the reperfusion period. Results: Muscle viability (102{\%} ± 10 PJ, 78{\%} ± 4 UN, P = 0.04), IL-B (21.1 ± 1.3 PJ, 15.5 ± 1.0 UN, P = 0.02), and IL-6 levels (16.3 ± 1.2 PJ, 10.9 ± 1.4 UN, P = 0.04) after 48 I/R were significantly higher in PJ. KC and MPO levels were higher in PJ but neither reached statistical significance. Conclusions: Post hoc PJ34 therapy appears to protect skeletal muscle from I/R injury despite increased levels of local cytokines. These initial findings support the role of local post hoc therapy in the treatment of acute limb threatening ischemia suggesting that further study of this novel therapy is warranted.",
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AU - Albadawi, Hassan

AU - Stone, David H.

AU - Crawford, Robert S.

AU - Entabi, Fateh

AU - Watkins, Michael T.

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AB - Background: PARP stabilizes DNA and modulates inflammation in murine models of sepsis, stroke, and myocardial infarction. Previous studies have shown that systemic PARP inhibition before hindlimb ischemia preserves tissue viability and modulates cytokine synthesis during reperfusion. The purpose of this study was to determine whether intra-muscular (IM) administration of PJ34, a potent inhibitor of PARP, after the onset of acute hindlimb ischemia (post hoc) modulates the local production of inflammatory mediators during ischemia/reperfusion (I/R). Materials and methods: The control tension tourniquet was used to establish unilateral hindlimb ischemia in mice for 3 h followed by 48 h I/R. The treatment group (PJ) received IM PJ34 (10 mg/kg) in the affected hindlimb 90 min into ischemia whereas the control group (UN) received IM saline (150 uL) at the same time point. Skeletal muscle viability (MTT mitochondrial activity), local neutrophil chemoattractant protein (KC), Interleukin 6 (IL-6), Interleukin 1β (IL-1β), and Myeloperoxidase (MPO) levels were measured in protein extracts after the reperfusion period. Results: Muscle viability (102% ± 10 PJ, 78% ± 4 UN, P = 0.04), IL-B (21.1 ± 1.3 PJ, 15.5 ± 1.0 UN, P = 0.02), and IL-6 levels (16.3 ± 1.2 PJ, 10.9 ± 1.4 UN, P = 0.04) after 48 I/R were significantly higher in PJ. KC and MPO levels were higher in PJ but neither reached statistical significance. Conclusions: Post hoc PJ34 therapy appears to protect skeletal muscle from I/R injury despite increased levels of local cytokines. These initial findings support the role of local post hoc therapy in the treatment of acute limb threatening ischemia suggesting that further study of this novel therapy is warranted.

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