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

Mark F Conrad, David H Stone, Hassan Albadawi, Fateh Entabi, Michael T Watkins
Massachusetts General Hospital, Boston, MA

Objective:PARP stabilizes DNA and modulates inflammation in murine models of sepsis, stroke and myocardial infarction. Previous studies have shown that systemic PARP inhibition prior to 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 reperfusion (I/R).
Design: Prospective controlled animal study.
Setting:
Medical school affiliated university hospital.
Patients: B6129SF2/J male mice.
Interventions: Unilateral hindlimb ischemia was established in mice for three hours followed by 48 hours I/R. The treatment group (PJ) received IM PJ34 (10mg/kg) in the affected hindlimb 90 minutes into ischemia while the control group (UN) received IM saline (150ul) at the same time point.
Main Outcome Measures: Skeletal muscle was evaluated for viability, local Interleukin-1B (IL-1B), Interleukin-6 (IL-6), Neutrophil Chemoattractant Protein (KC), and Myeloperoxidase (MPO).
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. This protection occurs despite increased levels of local mediators of inflammation suggesting that cytokine activity does not necessarily correlate with cellular injury severity. 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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