Organophosphate intoxication: effect of PARS inhibition

描述(由申请人提供)：激活聚(ADP)核糖合成酶(PARS)(也称为聚(ADP)核糖聚合酶或PARP)是氧化剂诱导的神经损伤的一种新机制。在DNA单链断裂的触发下，PARS催化ADP-核糖的高能量聚合，导致NAD耗竭，糖酵解和线粒体呼吸受抑，最终细胞内高能磷酸还原，导致神经元坏死。最近的初步数据表明，PARS通路在有机磷中毒相关的脑损伤中起作用：在大剂量使用PARS抑制剂苯甲酰胺的大鼠中，梭曼诱导的癫痫发作减少，脑损伤受到抑制。申请人正在开发一种新型的、专有的具有神经保护潜力的PARP抑制剂化合物。我们已经获得了证据表明，超强的PARS抑制剂可以减轻氧化剂诱导的细胞损伤。此外，在啮齿动物局部脑缺血-再灌注模型上的体内研究表明，这些化合物可以减轻再灌注损伤的程度。伊诺克的目的是开发其新型超高效PARS抑制剂系列的成员，作为治疗有机磷中毒相关神经损伤的药物。在最初的概念验证研究范围中，申请者与巴特尔医学研究和评估设施的研究人员提议(1)在丝氨酸和梭曼诱导的神经损伤的大鼠模型中测试他们的铅抑制剂。目前研究的另一个目的是(2)建立该化合物的治疗干预窗口。在这个模型中证实PARS抑制剂化合物的有效性和可接受的治疗窗口将鼓励该化合物作为治疗有机磷引起的神经毒性的额外的临床前和临床开发。基于PARS技术开发的一种神经保护剂，如果对有机磷中毒有效，预计将为平民人口提供好处(作为杀虫剂和农药相关疾病的辅助治疗，以及作为恐怖分子神经毒气袭击的对策)，还可能作为神经毒气对策的军事用途。

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.