Since NAD+ acts as the substrate for generation of ADP-ribose monomers, persistent activation of PARP can deplete the cell of ATP, perturbing cellular homeostasis and triggering cell death. Furthermore, activation of PARP has been shown to initiate various apoptotic signaling events. A 286982 Therefore, depending on the context and extent of PARP activation, it can either be beneficial or detrimental to cellular homeostasis. PARP inhibition has been successfully employed as a novel therapeutic strategy in cancer therapy to enhance the cytotoxic effects of DNA-damaging agents. ABT-888 is a novel and potent PARP-1 and PARP-2 inhibitor that has been shown to potentiate multiple DNA damaging agents including cisplatin, carboplatin, cyclophosphamide, and temozolomide and has currently progressed into human phase II clinical trials. Moreover, findings from a phase I clinical trial demonstrated that olaparib, another PARP inhibitor, increases antitumor efficacy of traditional chemotherapy with less adverse effects. While PARP inhibition has shown therapeutic benefit in cancer treatment, its application has also improved the outcome in a variety of neuropathological conditions including a model of diabetes. Compound 4a is the enantiomer of the clinical PARP inhibitor veliparib and is a potent inhibitor of both PARP-1 and 2 and has an EC50 of 3 nM in a cell based assay of PARP activity. The mouse pharmacokinetic profile of compound 4a is very similar to ABT-888 and demonstrates equivalent in vivo efficacy in mouse xenograft tumor models. In the current investigation, we hypothesized that the selective PARP inhibitor compound 4a would attenuate cisplatin and oxaliplatinassociated pain. Cancer related pain such as chemotherapy-induced painful neuropathy is a major morbidity caused by many commonly used chemotherapeutic agents for cancer therapy. Pain can be disabling, causing loss of functional abilities and decreased quality of life. Current therapeutic options for CIPN are largely limited to drugs approved for other pain conditions such as anticonvulsants, antidepressants, and opioids, which offer minimal relief. The clinically relevant goal of this study was to test whether a novel PARP inhibitor, compound 4a, can attenuate chemotherapyinduced neuropathic pain. Chemotherapy treatment with cisplatin or oxaliplatin produces painful neuropathy characterized by reduced thresholds to mechanical stimuli. Cisplatin reduced thresholds to heat, and in contrast, oxaliplatin reduced thresholds to cold stimuli. In this study we demonstrate that the novel and selective PARP-1/2 inhibitor, compound 4a, provides a protective effect AC 265347 against the functional sensory deficits, as measured by behavioral parameters induced by cisplatin and oxaliplatin treatment. The platinum drug doses used in this study are based on therapeutic doses that induce neuropathy in humans and mice and have antitumor activity in mice. As in humans, the cumulative dose and time course of administration predicts severity of associated sensory deficits in rodent studies after cisplatin and oxaliplatin treatment.