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: 8974379
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974379
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Animal Model; Animals; Antioxidants; Anxiety; Arthralgia; Attention; Biochemical; Biochemical Pathway; Biological; Biological Models; Brain imaging; Brain region; Bromides; Chemical Exposure; Chemicals; Chronic; Clinical; Cognition; Cognitive deficits; Conflict (Psychology); Data; Defect; Detection; Diagnostic; Environment; 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; Sleep disturbances; Stress; Superoxide Dismutase; Symptoms; Synapses; Synaptic plasticity; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Vertebral column; Veterans; Wild Type Mouse; antioxidant enzyme; anxiety sensitivity; base; behavioral study; 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; persistent symptom; 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年战争的700,000名军事人员中，有26％-32％的人遇到了慢性健康问题，这些问题定义不明，并且很难确定病原体。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，这些多症状健康问题称为海湾战争疾病。海湾战争后的二十多年，海湾战争退伍军人尚未解决许多症状，并且仍然没有一套可靠的诊断标准或有效的海湾战争疾病治疗方法。因此，迫切需要更好地了解疾病的固执性，并确定改善海湾退伍军人健康的更好方法。 海湾战争疾病的病因尚不清楚，但可能涉及海湾战争剧院所特有的各种化学物质以及身体和心理压力。几条临床发现支持海马中的缺陷，控制学习和记忆的大脑区域，海湾战争疾病中的缺陷以及缺陷包括较小的海马体积和低代谢，工作记忆中的缺陷以及慢性海马灌注功能障碍。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通过暴露于乙酰胆碱酯酶（ACHE）抑制剂（包括吡ido骨溴化物（PB），农药（苄氯菊酯）和神经药物）来解释。已经建立了许多动物模型，以模拟海湾战争化学物质和压力的暴露，这些模型中的神经认知缺陷再次表明海马受到参与。然而，海马缺陷下面的细胞和分子机制尚不完全清楚。 基于海湾战争剂的生物学特性，应激激素的已知作用以及暴露于GW药物的实验动物的数据，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。我们建议，慢性炎症和增加的氧化应激在海湾战争疾病的持续性中起着重要作用。因此，该应用的目的是进行试验研究，以确定各种海湾战争药物对海马功能的延迟和持久影响，以及神经炎症和氧化压力的参与，我们将使用野生型小鼠和野生型小鼠和小鼠具有较高的抗氧化酶，抗氧化酶，ecymexememem of Syromexem and ec-Sods and ec-Sods and ec-sods and ec-sod and ec-sod asod asod asod asod asod sod asod asod asod asod asod sy throuce Mode the the the ec-Sod，），），）海湾战争特工单独或结合在一起，以模拟海湾战争期间的状况。炎性细胞因子和糖皮质激素的水平将受到监测，以确定急性和慢性炎症和胁迫的水平。认知功能以及疼痛敏感性，焦虑和运动功能将在暴露于海湾战争药物后以各个间隔确定。为了识别组织和细胞水平的认知缺陷，我们将检查树突系统，该系统在海马形成过程中构成了在获取和记忆过程中获得和形成记忆过程中神经传递的基础设施。将研究树突状乔木，脊柱密度和形态，突触后蛋白以及生化途径对于维持树突系统很重要。图像分析以及免疫学和分子生物检测方法将用于确定突触系统中的结构，细胞和生化变化，以及这些变化如何影响突触和认知功能。