Anticholinesterase Neurotoxicity is Mediated by Oxidative Injury

氧化损伤介导抗胆碱酯酶神经毒性

• 批准号: 7496080
• 负责人: Dejan Milatovic
• 金额: $ 19.19万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496080
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Affect; Aging; Alzheimer' s Disease; Animal Model; Anti-Inflammatory Agents; Antioxidants; Area; Attenuated; Biochemical; Biological Markers; Brain; Brain Injuries; Carbamates; Cells; Cerebrum; Cessation of life; Chemical Warfare Agents; Cholinergic Agents; Cholinergic Receptors; Cholinesterase Inhibitors; Chromosome Pairing; Class; Clinical; Coenzyme Q10; Convulsions; Data; Development; Dinoprostone; Epilepsy; Event; Exposure to; Family; Generations; Gliosis; Glutamates; Hippocampus (Brain); Ibuprofen; Inflammatory; Inflammatory Response; Injury; Insecticides; Intoxication; Ischemic Stroke; Lead; Lipid Peroxidation; Lipid Peroxides; Mediating; Modeling; Molecular; Morbidity - disease rate; Motor Endplate; Muscle; Muscle fasciculation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuronal Injury; Neurons; Neuroprotective Agents; Nitric Oxide; Nitrogen; Numbers; Organophosphates; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pesticides; Population; Preventive; Production; Prophylactic treatment; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Purpose; Rattus; Reaction; Respiratory distress; Risk; Seizures; Signal Pathway; Signal Transduction; Symptoms; Synapses; System; Testing; Toxic effect; age related neurodegeneration; attenuation; base; cholinergic; cyclooxygenase 1; cyclooxygenase 2; cytokine; hippocampal pyramidal neuron; human WFDC2 protein; inorganic phosphate; mamantine; mortality; nerve agent; neuroinflammation; neuronal survival; neuropathology; neurotoxicity; novel; novel therapeutics; prevent; prophylactic; prostaglandin EP3 receptor; prostanoid receptor EP1; receptor; response; treatment effect

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.

描述（由申请方提供）：针对杀虫剂中毒或恐怖分子暴露于抗胆碱酯酶而急性给予的预防剂可预防中毒症状，包括肌束震颤、癫痫发作、惊厥和死亡。然而，抗胆碱酯酶药也具有长期未知的病理生理学作用，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、胆碱能神经元的激活和炎症反应诱导活性氧和活性氮的产生，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样的假设，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变性是促成神经变性的主要效应物。确定引起氧化损伤的许多效应物之间的精确关系将大大有助于神经保护剂的开发。在这里，我们建议使用生物化学和形态学的方法来测试假设，抑制氧化损伤和神经炎症的生物标志物可以防止抗胆碱酯酶神经毒性诱导的神经变性。我们将通过（1）确定抗胆碱酯酶暴露诱导神经元氧化损伤以及树突系统变性的新标志物变化的程度，（2）通过使用目前提出的抑制神经变性的神经保护剂，在抗胆碱酯酶神经毒性大鼠模型中检查神经元氧化损伤和树突变性的抑制（mamantine）、抗炎剂（布洛芬）和抗氧化剂产品，具有许多提出的作用，和（3）评估哪些马槟榔碱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。我们提出的假设，增加PGE 2是通过EP 2和EP 3受体信号传导的脑氧化损伤的调节剂。预期的结果将揭示关于抗胆碱酯酶诱导的脑损伤机制的新信息，保护或促进神经元存活的途径，并提出针对一类继续对全球数百万人构成重大风险的药物的新治疗策略。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型治疗策略，这类毒剂继续对全球数百万人构成重大风险。成功治疗的癫痫发作事件仍会导致显著的死亡率和发病率;因此，更好地了解脑损伤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。