Neuroinflammation, Oxidative Stress, and Hippocampal Defects in Gulf War Illness

海湾战争疾病中的神经炎症、氧化应激和海马缺陷

• 批准号: 8734750
• 负责人: Ting-Ting Huang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734750
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Animal Model; Animals; Antioxidants; Anxiety; Arthralgia; Attention; Behavioral; Biochemical; Biochemical Pathway; Biological; Biological Models; Brain imaging; Brain region; Bromides; Chemical Exposure; Chemicals; Chronic; Clinical; Cognition; Cognitive; Conflict (Psychology); Data; Defect; Detection; Diagnostic; Environment; Enzymes; Etiology; Exposure to; Fatigue; Functional disorder; Future; Glucocorticoids; Goals; Gulf War; Headache; Health; Health Status; Hippocampal Formation; Hippocampus (Brain); Hormones; Image Analysis; Impaired cognition; Inflammation; Inflammatory; Insecta; Insecticides; Knowledge; Lead; Learning; Maintenance; Mediator of activation protein; Memory; Mental Depression; Methods; Military Personnel; Modeling; Molecular; Monitor; Mood Disorders; Morphology; Motor; Mus; Myalgia; Nature; Neurocognitive; Neurologic; Neurons; Output; Oxidation-Reduction; Oxidative Stress; Pain; Pathogenesis; Pathway interactions; Perfusion; Permethrin; Pesticides; Physiological; Pilot Projects; Play; Property; Proteins; Psychological Stress; Research Design; Research Infrastructure; Role; Sarin; Short-Term Memory; Simulate; Sleep disturbances; Stress; Superoxide Dismutase; Symptoms; Synapses; Synaptic plasticity; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Vertebral column; Veterans; Wild Type Mouse; base; chronic pain; cognitive function; cohort; cytokine; density; design; disturbance in affect; effective therapy; epidemiology study; extracellular; gastrointestinal; improved; mouse model; nerve agent; neurogenesis; neuroinflammation; neurotransmission; novel; pyridostigmine; stressor; synaptic function; translational study

DESCRIPTION (provided by applicant): Of the 700,000 military personnel deployed to the 1990-1991 Gulf War, 26%-32% developed chronic health problems that are ill-defined and in which it is difficult to pinpoint the etiologicl agents. The health problems include chronic fatigue, muscle and joint pains, gastrointestinal problems, sleep disturbances, mood disorders, persistent headaches, and attention and memory problems. Collectively, these multi-symptom health problems are called Gulf War illness. Twenty plus years after the Gulf War, many of the symptoms have not been resolved in Gulf War Veterans, and there is still not a reliable set of diagnostic criteria or effective treatments for Gulf War illness. Therefore, there is an urgent need for a better understanding of the stubborn nature of the illness and identify better approaches to improve the health of Gulf War Veterans. The etiology of the Gulf War illness is not known, but likely involves various chemicals and physical and psychological stresses unique to the Gulf War Theater. Several lines of clinical findings support defects in the hippocampus, the brain region that controls learning and memory, in Gulf War illness, and the defects include smaller hippocampal volume and hypometabolism, defects in working memory, and chronic hippocampal perfusion dysfunction. Increasing evidence suggests that neurological defects in Gulf War illness can be explained in part by exposure to acetylcholinesterase (AChE) inhibitors, including pyridostigmine bromide (PB), pesticides (permethrin), and nerve agents. A number of animal models have been established to simulate exposures to Gulf War chemicals and stress, and neurocognitive defects in these models again suggest the involvement of hippocampus. However, the cellular and molecular mechanism(s) underlying hippocampal defects is not entirely clear. Based on the biological properties of Gulf War agents, the known effects of stress hormones, and data from experimental animals exposed to GW agents, chronic inflammation and elevated levels of oxidative stress are likely to be intimately involved in Gulf War illness. We propose that chronic inflammation and increased oxidative stress play an important role in the persistent nature of Gulf War illness. Therefore, the goal of this applicatio is to carry out a pilot study to ascertain the delayed and persistent effects of various Gulf War agents on hippocampal functions and the involvement of neuroinflammation and oxidative stress We will use wild type mice and mice with higher levels of the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), as the model system and expose the mice repeatedly to various Gulf War agents alone or in combination to simulate the condition during the Gulf War. The level of inflammatory cytokines and glucocorticoid hormone will be monitored to ascertain the level of acute and chronic inflammation and stress. Cognitive functions, together with pain sensitivity, anxiety, and motor functions, will be determined at various intervals following exposure to Gulf War agents. To identify cognitive defects at the tissue and cellular level, we will examine the dendritic system, which forms the infrastructure for neurotransmission during acquisition and formation of memory, in the hippocampal formation. Dendritic arbors, spine density and morphology, post-synaptic proteins, and the biochemical pathway important for the maintenance of the dendritic system will be investigated. Image analyses and immunological and molecular biological detection methods will be used to identify the structural, cellular, and biochemical changes in the synaptic system and how those changes may impact synaptic and cognitive functions.

描述(由申请人提供)： 在部署到1990-1991年海湾战争中的70万名军事人员中，26%-32%的人患上了定义模糊的慢性健康问题，很难确定病因。健康问题包括慢性疲劳、肌肉和关节疼痛、胃肠道问题、睡眠障碍、情绪障碍、持续性头痛以及注意力和记忆问题。总的来说，这些多症状的健康问题被称为海湾战争疾病。海湾战争20多年后，海湾战争退伍军人的许多症状仍未得到解决，海湾战争疾病仍没有一套可靠的诊断标准或有效的治疗方法。因此，迫切需要更好地了解这种疾病的顽固性，并确定更好的方法来改善海湾战争退伍军人的健康。海湾战争疾病的病因尚不清楚，但可能涉及海湾战争战区特有的各种化学物质和生理和心理压力。有几条临床发现支持海湾战争疾病中控制学习和记忆的大脑区域海马体存在缺陷，这些缺陷包括海马体体积较小和代谢不足，工作记忆缺陷，以及慢性海马体灌流功能障碍。越来越多的证据表明，海湾战争疾病中的神经缺陷可以部分解释为暴露于乙酰胆碱酯酶(AChE)抑制剂，包括吡斯的明(PB)、杀虫剂(氯菊酯)和神经毒剂。已经建立了一些动物模型来模拟海湾战争化学品和压力的暴露，这些模型中的神经认知缺陷再次表明海马体参与其中。然而，导致海马区缺陷的细胞和分子机制(S)还不完全清楚。根据海湾战争战剂的生物学特性、应激激素的已知影响以及暴露于GW战剂的实验动物的数据，慢性炎症和氧化应激水平升高可能与海湾战争疾病密切相关。我们认为，慢性炎症和氧化应激增加在海湾战争疾病的持续性中起着重要作用。因此，本应用的目的是开展一项初步研究，以确定各种海湾战剂对海马区功能的延迟和持续影响以及神经炎症和氧化应激的参与。我们将以野生型小鼠和抗氧化酶-细胞外超氧化物歧化酶(EC-SOD)水平较高的小鼠为模型系统，并重复将小鼠单独或联合暴露于各种海湾战剂，以模拟海湾战争期间的情况。将监测炎症细胞因子和糖皮质激素的水平，以确定急性和慢性炎症和应激的水平。认知功能，以及疼痛敏感性、焦虑和运动功能，将在接触海湾战争特工后的不同时间段确定。为了在组织和细胞水平上识别认知缺陷，我们将检查海马结构中的树突系统，它构成了记忆获得和形成过程中神经传递的基础设施。将研究树枝、棘突密度和形态、突触后蛋白以及对维持树突系统重要的生化途径。图像分析以及免疫学和分子生物学检测方法将用于识别突触系统的结构、细胞和生化变化，以及这些变化可能如何影响突触和认知功能。