Organophosphate intoxication: effect of PARS inhibition

描述（由申请人提供）：多（ADP）核糖合成酶（PARS）（也称为多（ADP）核糖聚合酶或PARP）的激活是氧化诱导神经损伤的新机制。由DNA单链断裂触发，PARS催化adp核糖的能量消耗聚合，导致NAD耗竭，糖酵解和线粒体呼吸受到抑制，细胞内高能磷酸盐最终减少，导致神经元坏死。最近的初步数据表明，PARS通路在有机磷毒性相关的脑损伤中起作用：在使用高剂量PARS抑制剂苯甲酰胺治疗的大鼠中，索曼诱发的癫痫发作减少，脑损伤得到抑制。申请人正在开发一种新颖的、专有的PARP抑制剂化合物，具有神经保护潜力。我们已经获得的证据表明，超强的PARS抑制剂可以减少氧化诱导的细胞损伤。此外，啮齿动物局部脑缺血再灌注模型的体内研究表明，这些化合物可以减轻再灌注损伤的程度。Inotek的目的是开发其新型超高效PARS抑制剂系列的一种成员，作为治疗有机磷毒性相关神经损伤的药物。在最初的概念验证研究范围内，申请人与巴特尔医学研究和评估机构的研究人员一起提议(1)在丝氨酸和梭曼诱导的神经损伤大鼠模型中测试他们的先导抑制剂。当前研究的另一个目的是(2)建立该化合物干预的治疗窗口。在该模型中确认PARS抑制剂化合物的疗效和可接受的治疗窗口，将鼓励该化合物作为治疗有机磷诱导的神经毒性的额外临床前和临床开发。基于PARS技术开发的一种神经保护剂，如果对有机磷毒性有效，预计将造福平民（作为杀虫剂和农药相关疾病的辅助治疗，以及作为恐怖主义神经毒气袭击的对策），并可能作为神经毒气对策在军事上使用。

DESCRIPTION (provided by applicant): 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.