Immune basis for hippocampal cholinergic deficits in pyridostigmine-treated rats

吡斯的明治疗大鼠海马胆碱能缺陷的免疫基础

• 批准号: 10515669
• 负责人: LAWRENCE P REAGAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515669
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Affect; Animal Model; Arrhythmia; Behavior; Behavioral; Brain; Bromides; Cardiovascular Physiology; Cardiovascular system; Central Nervous System; Cholinesterases; Chronic; Diagnosis; Disease; Etiology; Exhibits; Exposure to; Functional disorder; Funding; Goals; Gulf War; Gulf War veteran; Hippocampus; Immune; Immune response; Inflammatory; Lead; Lipopolysaccharides; Measures; Microdialysis; Microglia; Modeling; Nature; Neurocognitive Deficit; Neuroimmune; Neurosecretory Systems; Performance; Persian Gulf Syndrome; Plasma; Prefrontal Cortex; Rattus; Recording of previous events; Rodent Model; Stimulus; Stress; Stressful Event; Symptoms; Telemetry; Testing; Therapeutic Intervention; Veterans; associated symptom; behavior measurement; behavior test; behavioral response; cholinergic; cytokine; experience; heart rate variability; in vivo; neurochemistry; neuroinflammation; novel; physiologic stressor; pressure; pyridostigmine; response; restraint stress; social stress; social stressor; stress reactivity

Following return from the Gulf War (GW), veterans have experienced of a constellation of symptoms, designated Gulf War Illness (GWI), that cannot be associated with a single disease. In this regard, GW veterans exhibit structural and functional deficits in the central nervous system (CNS), along with cardiovascular complications. One of the more insidious aspects of GWI is that it is a chronic and progressive disorder; indeed, the number of veterans diagnosed with GWI continues to rise in the post- deployment period. Although the mechanisms underlying the myriad of symptoms associated with GWI remain to be elucidated, some studies have determined that GWI veterans exhibit exaggerated immune responses to physiological stressors, which when combined with other studies support the concept that neuroinflammation is a key component in the etiology and progression of GWI. During the previous funding period we developed a rodent model of GWI in which rats were administered the acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB) alone and in combination with repeated restraint stress (RRS). Our ongoing studies have revealed that PB and RRS elicit alterations in cardiovascular, neuroendocrine, neuroimmune and behavioral measures. Perhaps more importantly, our preliminary studies indicate that these PB+RRS-induced alterations are exacerbated by lipopolysaccharide (LPS) or acute exposure to heterogeneous social stressors. Such observations suggest that in addition to baseline differences, a prior history of PB and stress may predispose GWI veterans to exaggerated responses to immune challenges or stressful life experiences after deployment in the GW. Surprisingly, relatively few studies have directly tested this hypothesis to determine the underlying mechanisms responsible for exacerbated responses to stress or immune challenges after exposure to PB. Accordingly, the goal of this project is to directly test our overarching hypothesis that immune challenges and stressful stimuli lead to exacerbated neuroimmune, neurochemical, cardiovascular and behavioral deficits after exposure to cholinesterase inhibition in an animal model of Gulf War Illness. This hypothesis will be tested in the following Aims: • Aim 1 will examine whether immune or stress challenges lead to potentiated neuroimmune responses in PB+RRS rats • Aim 2 will determine whether LPS or to exposure social stress enhances cardiovascular complications in enhanced in PB+RRS rats. • Aim 3 will determined whether the performance of hippocampal and prefrontal cortex-dependent behaviors are adversely affected by LPS administration or acute social stress. Successful completion of these studies will demonstrate that PB treatment in combination with stress elicits fundamental alterations in brain and body responses that may be much more evident following immune and social stress challenges, which would be highly consistent with the progress nature of GWI pathophysiology. Most importantly, these studies will identify loci for therapeutic intervention that can be quickly tested in our model and implemented for the treatment of GWI in our veterans.

从海湾战争（GW）返回后，退伍军人经历了一系列症状， 海湾战争病（GWI），不能与单一疾病相关联。在这方面，GW 退伍军人表现出中枢神经系统（CNS）的结构和功能缺陷，沿着 心血管并发症GWI的一个更阴险的方面是，它是一个慢性的， 在《易经》中，有一种说法是：“君子之道，焉可诬也？ 部署期间。尽管与GWI相关的无数症状的潜在机制 仍有待阐明，一些研究已经确定，GWI退伍军人表现出夸大的免疫反应， 对生理压力的反应，当与其他研究相结合时，支持这一概念， 神经炎症是GWI的病因学和进展的关键组成部分。 在上一个资助期间，我们开发了一种GWI的啮齿动物模型， 乙酰胆碱酯酶（AChE）抑制剂溴化吡啶斯的明（PB）单独使用和与 重复束缚应激（RRS）。我们正在进行的研究表明，PB和RRS引起的改变， 心血管、神经内分泌、神经免疫和行为测量。更重要的是，我们 初步研究表明，这些PB+ RRS诱导的改变被脂多糖加重 (LPS)或严重暴露于不同的社会压力源。这些观察表明，除了 基线差异，PB和压力的既往史可能使GWI退伍军人容易夸大 在GW中部署后对免疫挑战或压力生活经历的反应。令人惊奇的是， 相对较少的研究直接测试了这一假设，以确定潜在的机制 在暴露于PB后，负责加剧对压力或免疫挑战的反应。因此，委员会认为， 该项目的目标是直接测试我们的总体假设，即免疫挑战和压力 刺激导致神经免疫、神经化学、心血管和行为缺陷恶化， 在海湾战争疾病的动物模型中暴露于胆碱酯酶抑制剂。这一假设将得到检验 在以下目标中： ·目标1将检查免疫或压力挑战是否会导致增强的神经免疫反应， PB+RRS大鼠 ·目标2将确定LPS或暴露于社会压力是否会增加心血管并发症， 增强PB+RRS大鼠。 ·目标3将确定海马和前额叶皮质依赖性的表现 行为受到LPS施用或急性社会应激的不利影响。 这些研究的成功完成将证明PB治疗与应激增强相结合 大脑和身体反应的根本改变，在免疫和 社会压力挑战，这将与GWI的进步性质高度一致 病理生理学最重要的是，这些研究将确定治疗干预的位点， 在我们的模型中迅速进行了测试，并在退伍军人中实施了GWI的治疗。