Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme which binds to and is activated by breaks in DNA. During ischemic injury and reperfusion, increased high levels of reactive oxygen species are generated that mediate cellular damage including lipid peroxidation, protein denaturation and DNA breaks. DNA damage can be so extensive, that PARP-1 is over-activated, leading to ATP depletion, cell death, and tissue injury. Pharmacological inhibition of PARP-1 is a novel approach for the treatment of ischemic conditions including ischemic stroke and myocardial infarction and in the treatment of acute liver failure.
In addition to inhibiting PARP-1 during reperfusion injury, inhibition of PARP-1 during inflammation is also of therapeutic benefit. This is due to PARP-1’s role as trans-activator of NF-κB, AP-1 and other transcriptional activators of inflammatory gene expression, such as TNF-α, iNOS, and ICAM-1. These data suggest that PARP-1 inhibitors not only limit primary necrosis but also secondary necrosis initiated by inflammatory cell injury. PARP inhibitors are therefore also considered to have potential use in treating sepsis, septic shock and inflammation.
