Anticholinesterase Neurotoxicity is Mediated by Oxidative Injury

说明(申请人提供)：针对杀虫剂中毒或恐怖分子接触抗胆碱酯酶而急性给予的预防性药物可以预防中毒症状，包括痉挛、癫痫、抽搐和死亡。然而，抗胆碱酯酶也具有长期未知的病理生理效应，使得合理的预防/治疗成为问题。越来越多的证据表明，过度的胆碱能刺激、谷氨酸能神经元的激活和炎症反应诱导了活性氧和氮的产生，导致神经元变性。来自患者大脑和动物模型的数据广泛支持这一假说，即衰老中的神经元氧化损伤以及伴随阿尔茨海默病、缺血性中风和癫痫的神经退行性变是导致神经退行性变的主要因素。确定导致氧化损伤的许多效应器之间的精确关系将极大地帮助神经保护剂的开发。在这里，我们建议使用生化和形态学方法来检验假设，即抑制氧化损伤和神经炎症的生物标记物可以防止在抗胆碱酯酶神经毒性中诱导的神经变性。我们将通过(1)确定抗胆碱酯酶暴露在多大程度上诱导神经元氧化损伤的新标记物以及树突状系统的退化来实现这一目标，(2)通过使用目前提出的抑制神经变性的神经保护剂(马马汀)、抗炎药(布洛芬)和具有一系列拟议作用的抗氧化剂产品来检测在抗胆碱酯酶诱导的癫痫大鼠模型中抑制神经元氧化损伤和树突状细胞退化的作用，以及(3)评估哪些前列腺素受体参与增强或抑制抗胆碱酯酶诱导的癫痫发作后的脑氧化损伤。我们建议通过EP2和EP3受体信号来检验PGE2升高是大脑氧化损伤的调节因子的假说。预期的结果将提供关于抗胆碱酯酶诱导的脑损伤的机制、保护或促进神经元存活的途径的新信息，并针对一类继续对全球数百万人构成重大风险的药物提出新的治疗策略。这些研究的目的是利用各种独立的实验策略来研究针对农药和神经毒剂暴露的新治疗策略，这类毒剂继续对全球数百万人构成重大风险。因此，更好地了解脑损伤的机制和保护或促进神经元存活的途径，对于开发与农药和神经毒剂暴露相关的有效治疗和预防性治疗至关重要。

DESCRIPTION (provided by applicant): Prophylactic agents acutely administered in response to insecticide intoxication or terrorist exposure to anticholinesterases can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have longer-term unknown pathophysiological effects making rational prophylaxis/treatment problematic. Increasing evidence suggests that excessive cholinergic stimulation, activation of glutamatergic neurons and inflammatory response induces generation of reactive oxygen and nitrogen species, leading to neuronal degeneration. Data from patients' brains and animal models have widely supported the hypothesis that neuronal oxidative damage in aging as well as neurodegeneration accompanying Alzheimer's disease, ischemic stroke and epilepsy, is a major effector contributing to neurodegeneration. Determining the precise relationships among many effectors that cause oxidative damage will greatly aid in the development of neuroprotective agents. Here we propose to use biochemical and morphologic approaches to test hypothesis that suppression of biomarkers of oxidative damage and neuroinflammation can prevent neurodegeneration induced in anticholinesterase neurotoxicity. We will achieve this objective by (1) determining the extent to which anticholinestrease exposure induce changes in novel markers of neuronal oxidative damage as well as degeneration of the dendritic system, (2) examining suppression of neuronal oxidative damage and dendritic degeneration in rat model of anticholineterase neurotoxicity by using neuroprotectants currently proposed to suppress neurodegeneration (mamantine), anti- inflammatory agent (ibuprofen) and antioxidant products with a number of proposed actions, and (3) evaluating which prostaglandine receptors are involved in enhancement or suppression of cerebral oxidative damage following anticholinesterase-induced seizures. We propose to test hypothesis that increased PGE2 is a regulator of cerebral oxidative damage by signaling through EP2 and EP3 receptors. Anticipated results will shed novel information on mechanisms of anticholinesterase-induced brain injury, pathways that protect or promote neuronal survival, and suggest novel therapeutic strategies against a class of agents that continues to pose a significant risk for millions of people worldwide. The purpose of these studies is to utilize a variety of independent experimental strategies to investigate novel therapeutic strategies against pesticide and nerve agents exposure, a class of agents that continues to pose a significant risk for millions of people worldwide. Event successfully treated seizures still results in significant mortality and morbidity; therefore, better understanding of the mechanisms of brain injury and pathways that protect or promote neuronal survival, are essential for development of efficacious treatments and preventive therapies associated with pesticide and nerve agents exposures.