High‐content screening identifies inhibitors of oxidative stress‐induced parthanatos: cytoprotective and anti‐inflammatory effects of ciclopirox

Background and Purpose Excessive oxidative stress can induce PARP1-mediated programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array diseases associated with tissue injury inflammation. Our goal was to identify novel molecules inhibiting Experimental Approach A small library 774 pharmacologically active compounds screened Sytox Green uptake assay, which identified 20 hits that reduced hydrogen-peroxide-induced an efficiency comparable the benchmark PARP inhibitor, PJ34. Key Results Of these hits, two compounds, antifungal ciclopirox dopamine receptor agonist apomorphine, inhibited PAR polymer synthesis. These prevented binding PARP1 oxidatively damaged DNA but did not directly interfere interaction between PARP1. Both mitochondrial superoxide H2O2 production suppressed breakage. Since H2O2-induced damage is dependent on Fe2+-catalysed hydroxyl radical (Fenton chemistry), we determined iron chelation activity test found and, lesser extent, apomorphine act as chelators. We also show Fe2+ indirect inhibitory effects translate anti-inflammatory actions demonstrated mouse dermatitis model, where ear swelling, inflammatory recruitment poly(ADP-ribosyl)ation. Conclusion Implications findings indicate antimycotic drug, ciclopirox, acts chelator thus targets early event Ciclopirox has potential repurposed cytoprotective agent.