Activation of poly (ADP)ribose synthetase (PARS) (also known as poly(ADP)ribose polymerase or PARP) is a novel mechanism of oxidant-induced neuroinjury. Triggered by DNA single strand breakage, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates, leading to neuronal necrosis. Recent preliminary data indicate that the PARS pathway is operative in organophosphate toxicity related brain damage: in rats treated with high doses of the PARS inhibitor benzamide, soman-induced seizures were reduced and brain damage was suppressed. The applicants are developing a novel, proprietary class of PARP inhibitor compounds with neuroprotective potential. We have obtained evidence that ultrapotent PARS inhibitors reduce oxidant-induced cellular injury. Furthermore in vivo studies in rodent models of regional cerebral ischemia-reperfusion demonstrate that the compounds reduce the degree of reperfusion injury. Inotek's intention is to develop a member of its novel series of ultrapotent PARS inhibitors as a drug for the treatment of organophosphate toxicity related neuroinjury. In an initial, proof-of concept scope of research, the applicants, together with investigators at Battelle Medical Research and Evaluation Facility, propose (1) to test their lead inhibitor and in rat models of serin and soman induced neuroinjury. An additional aim of the current studies is (2) to establish the therapeutic window of intervention with the compound. Confirmation of the efficacy and acceptable therapeutic window of the PARS inhibitor compound in this model will encourage additional pre-clinical and clinical development of the compound as a treatment of organophosphate induced neurotoxicity. A neuroprotective agent, developed based on the PARS technology, if efficacious against organophosphate toxicity, is expected to provide benefit for civilian populations (as adjunct therapy for insecticide and pesticide related illnesses, and as a countermeasure for terrorist nerve gas attacks), and also has a potential military use as a nerve gas countermeasure. ? ? ?
