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

描述（由申请人提供）： 在1990-1991年海湾战争中部署的700，000名军事人员中，26%-32%的人患有慢性健康问题，这些问题定义不清，难以确定病因。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力问题。这些多症状的健康问题统称为海湾战争疾病。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，仍然没有一套可靠的诊断标准或海湾战争疾病的有效治疗方法。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，但可能涉及各种化学品和海湾战争战区特有的生理和心理压力。一些临床发现支持海湾战争疾病中海马体（控制学习和记忆的脑区）的缺陷，这些缺陷包括海马体体积较小和代谢减退、工作记忆缺陷和慢性海马体灌注功能障碍。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解释为暴露于乙酰胆碱酯酶（AChE）抑制剂，包括溴化吡啶斯的明（PB），杀虫剂（氯菊酯）和神经毒剂。已经建立了许多动物模型来模拟暴露于海湾战争的化学物质和压力，这些模型中的神经认知缺陷再次表明海马体的参与。然而，海马缺陷的细胞和分子机制尚不完全清楚。 根据海湾战争制剂的生物学特性、应激激素的已知效应以及暴露于GW制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发挥着重要作用。因此，本申请的目的是进行初步研究，以确定各种海湾战争制剂对海马功能的延迟和持续作用以及神经炎症和氧化应激的参与。我们将使用野生型小鼠和具有较高水平的抗氧化酶、细胞外超氧化物歧化酶（EC-SOD）的小鼠，作为模型系统，并将小鼠反复暴露于单独或组合的各种海湾战争制剂，以模拟海湾战争期间的条件。将监测炎性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，将在暴露于海湾战争制剂后的不同时间间隔进行测定。为了在组织和细胞水平上识别认知缺陷，我们将研究海马结构中的树突状系统，该系统在记忆的获得和形成过程中形成神经传递的基础结构。树突状乔木，棘密度和形态，突触后蛋白，和生物化学途径的树突状系统的维护将进行调查。图像分析和免疫学和分子生物学检测方法将用于识别突触系统中的结构，细胞和生化变化以及这些变化如何影响突触和认知功能。

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.