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. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when it is given at reperfusion after MCAO. However, no studies of MCAO have tested PARP inhibitors in aged animals known to have a senescent immunologic system and diminished protection by sex hormones. Because aged animals are thought to be more translationally relevant for the human stroke population, a PARP inhibitor should be tested in aged animals of both sexes before moving into clinical stroke trials. We propose testing the PARP inhibitor veliparib at reperfusion after MCAO in aged male and female mice based on its good brain penetration and its established safety in human oncology trials. Our planned primary outcome is one-month performance on a reaching-to-grasp dexterity task known to display sustained deficits for over a month after stroke. Secondary outcomes include short-term deficits in four other sensorimotor tasks, fear conditioning cognition at one month, brain atrophy at one month, and acute MRI determinations of lesion volume, CBF, and mismatch of DTI with tissue pH maps. The team is led by a PI with 30 years of experience in performing preclinical studies of MCAO, neuroscientists who elucidated parthanatos signaling in models of excitotoxicity and stroke, a stroke clinician with expertise in neurobehavior testing in mice after stroke, an MR scientist with 25 years of experience in developing new modalities of brain imaging for use in stroke and other disorders, and a MR scientist with expertise in multimodal MR imaging in rodents. The team has a long history of collaborating together on experimental stroke and is highly dedicated to the scientific rigor of the SPAN mission by serving as a test site for six candidate drugs for adjunct use with reperfusion therapies in ischemic stroke.
Despite recent advances in removal of blood clots from large cerebral arteries in patients suffering from a stroke that have allowed restoration of blood flow to the brain and improved outcome, a portion of these patients still suffer poor neurological outcome or death. Using experimental models of stroke, we intend to participate in the Stroke Preclinical Assessment Network to evaluate the efficacy of candidate drugs that could be administered as an adjunct therapy with clot removal or lysis therapy. We propose that one of the drugs should be an inhibitor of the enzyme poly(ADP-ribose)polymerase that we and many others have shown to contribute to neuronal cell death and neuroinflammation after stroke.
