Targeting Parthanatos in Ischemic Stroke

Abstract

Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4–6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-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 most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.

14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos

“…Parthanatos is a unique form of cell death that is mediated by poly ADP-ribose polymerase (PARP) and is completely different from programmed cell apoptosis. It is widely involved in cell oxidative damage and the pathological processes of neurodegenerative disease [ 5 , 6 , 7 ]. The parthanatos inhibitor is neuroprotective against ischemic stroke that works by suppressing neuroinflammation and matrix metaloproteinase-9 expression and reducing blood–brain barrier damage [ 8 ].…”

Application of Regulatory Cell Death in Cancer: Based on Targeted Therapy and Immunotherapy

“…can also induce PARP1 activation ( 148 , 149 ) ( Figure 2 ). Parthanatos is involved in several important pathological processes, including ischemia-reperfusion injury after cerebral ischemia or myocardial infarction ( 150 , 151 ), and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease ( 152 ).…”

Molecular Mechanisms of Parthanatos and Its Role in Diverse Diseases

“…Parthanatos is involved in MCAO/R-induced model animals, which used different PARP inhibitors (PJ-34, olaparib, 3-AB, DPQ, INO-1001, FR247304, DR2313, MP-24, HY-DAMTIQ) or PARP1-null mice (PARP1 −/− ) [163,164]. The oxygen-glucose deprivation (OGD)-injured mesenchymal stem cells (MSCs) neuron model is used to reveal that coculturing with MSCs protects the cortical neurons from OGD-induced parthanatos by alleviating AIF nucleus translocation [7].…”