Postischemic poly (ADP-ribose) polymerase (PARP) inhibition reduces ischemia reperfusion injury in a hind-limb ischemia model

Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Surgery (Impact Factor: 3.38). 07/2010; 148(1):110-8. DOI: 10.1016/j.surg.2009.12.006
Source: PubMed


Several experiments were designed to determine whether the systemic, postischemic administration of PJ34,which is a poly-adenosine diphosphate (ADP)-ribose polymerase inhibitor, decreased tissue injury and inflammation after hind-limb ischemia reperfusion (I/R).
C57BL6 mouse limbs were subjected to 1.5 h ischemia followed by 24-h reperfusion. The treatment group (PJ) received intraperitoneal PJ34 (30 mg/kg) immediately before reperfusion, as well as 15 min and 2 h into reperfusion. The control group (CG) received lactated Ringer's alone at the same time intervals as PJ34 administration. The skeletal muscle levels of adenosine triphosphate (ATP), macrophage inflammatory protein-2 (MIP-2), keratinocyte derived chemokine (KC), and myeloperoxidase (MPO) were measured. Quantitative measurement of skeletal muscle tissue injury was assessed by microscopic analysis of fiber injury.
ATP levels were higher in limbs of PJ versus CG mice (absolute ATP: 4.7 +/- 0.35 vs 2.3 +/- 0.15-ng/mg tissue, P = .002). The levels of MIP-2, KC, and MPO were lower in PJ versus CG mice (MIP-2: 1.4 +/- 0.34 vs 3.67 +/- 0.67-pg/mg protein, P = .014; KC: 4.97 +/- 0.97 vs 12.65 +/- 3.05-pg/mg protein, P = .037; MPO: 46.27 +/- 10.53 vs 107.34 +/- 13.58-ng/mg protein, P = .008). Muscle fiber injury was markedly reduced in PJ versus CG mice (4.25 +/- 1.9% vs 22.68 +/- 3.0% total fibers, P = .0004).
Systemic postischemic administration of PJ34 preserved skeletal muscle energy levels, decreased inflammatory markers, and preserved tissue viability post-I/R. These results support PARP inhibition as a viable treatment for skeletal muscle I/R in a clinically relevant post hoc scenario.

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Available from: Hassan Albadawi
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    • "It is difficult to relate the present in vitro findings to the in vivo administration of PJ-34 since, to the best of our knowledge, the actual plasma concentration of this drug and its final redistribution to the brain tissue remain unclear. Since the dose of PJ-34 injected into experimental animal is 3-30 mg/kg (Abdelkarim et al., 2001; Virág and Szabó, 2002; Kauppinen et al., 2009; Crawford et al., 2010), assuming uniform drug distribution throughout body compartments of an adult rat (and ignoring any bound fraction that might lower the free drug concentration), one might estimate a plasma concentration of approximately 37 mM after 10 mg/kg, that is in the range of the concentrations tested in vitro in the present report. Even if the actual concentration of free PJ-34 at neuronal membrane level is likely to be lower, it seems feasible that it would still be compatible with those tested in the present study. "
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