Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP), which then stimulates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor (AIF) from the outer mitochondrial membrane. In the cytosol, AIF forms a complex with macrophage migration inhibitory factor (MIF) that translocates into the nucleus where the MIF degrades DNA and produces cell death. A review of the literature reveals 23 publications that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO) based on the use of 9 different PARP inhibitors (19 studies) or PARP1 null mice (6 studies) from 13 different labs. Several studies indicate a therapeutic window of 4-6 h after MCAO. In young female rats, 2 studies from 2 labs support a role for parthanatos based on the use of 2 different PARP inhibitors, whereas 2 studies from one lab do not support a role in young female PARP1 null mice. In addition to parthanatos-mediated neuronal cell death, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NFkB transcription in microglia, suppressing MMP-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Thus, PARP inhibitors may be of benefit in stroke through action on at least two major mechanisms: 1) inhibiting a prominent form of programmed necrosis, and 2) ameliorating neuroinflammation and blood-brain barrier damage. 

Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective in young animals, even when it is given at reperfusion after MCAO. However, no studies of focal ischemic stroke have tested PARP inhibitors in aged animals known to have a senescent immunologic system and diminished protection by sex hormones. In addition, PARP inhibitors have yet to be tested in stroke models in animals with chronic hypertension, diabetes or other comorbidities. Evaluation in stroke models with comorbidities will be important before moving into clinical stroke trials.

Several third generation PARP inhibitors have entered clinical oncology trials without major adverse effects and could be repurposed for stroke. We propose testing the third generation PARP inhibitor veliparib at reperfusion after middle cerebral artery occlusion. This choice was based on its good brain penetration, its anti-inflammatory efficacy in models of traumatic brain injury, and its established safety with 30-day administration in human oncology trials.