Organophosphate intoxication: effect of PARS inhibition

有机磷中毒：PARS 抑制作用

• 批准号: 6738690
• 负责人: Zsuzsanna Kinga Zsengeller
• 金额: $ 24.03万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2005-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738690
• 关键词: cholinesterase inhibitors; cytotoxicity; disease /disorder model; drug design /synthesis /production; electroencephalography; enzyme inhibitors; histopathology; insecticides; laboratory rat; nerve gas; nerve injury; neuroprotectants; pentosyltransferase

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.

描述（由申请人提供）：聚（ADP）核糖合成酶（PARS）（也称为聚（ADP）核糖聚合酶或PARP）的激活是氧化剂诱导的神经损伤的一种新机制。由DNA单链断裂触发，PARS催化ADP-核糖的能量消耗聚合，导致NAD耗尽，糖酵解和线粒体呼吸抑制，以及细胞内高能磷酸盐的最终减少，导致神经元坏死。最近的初步数据表明，PARS途径在有机磷毒性相关的脑损伤中起作用：在用高剂量PARS抑制剂苯甲酰胺治疗的大鼠中，梭曼诱导的癫痫发作减少，脑损伤受到抑制。申请人正在开发具有神经保护潜力的新型专有PARP抑制剂化合物。我们已经获得的证据表明，超强效PARS抑制剂减少氧化剂诱导的细胞损伤。此外，在啮齿动物局部脑缺血-再灌注模型中的体内研究表明，所述化合物降低了再灌注损伤的程度。Inotek的目的是开发其新型系列的超强效PARS抑制剂中的一员，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中，申请人与Battelle医学研究和评估机构的研究人员一起提出：（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。当前研究的另一个目的是（2）建立化合物干预的治疗窗口。PARS抑制剂化合物在该模型中的功效和可接受的治疗窗的确认将鼓励该化合物作为有机磷酸盐诱导的神经毒性的治疗的额外临床前和临床开发。基于PARS技术开发的神经保护剂，如果对有机磷酸盐毒性有效，预计将为平民群体提供益处（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），并且还具有作为神经毒气对策的潜在军事用途。