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: 10060733
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10060733
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Affect; Animal Model; Behavior; Behavioral; Brain; Bromides; Cardiovascular Physiology; Cardiovascular system; Cholinesterases; Chronic; Diagnosis; Disease; Etiology; Exhibits; Exposure to; Functional disorder; Funding; Goals; Gulf War; Gulf War veteran; Hippocampus (Brain); Immune; Immune response; Inflammatory; Lead; Life Experience; Lipopolysaccharides; Measures; Microdialysis; Microglia; Modeling; Nature; Neuraxis; Neurocognitive Deficit; Neuroimmune; Neurosecretory Systems; Performance; Persian Gulf Syndrome; Plasma; Prefrontal Cortex; Quick Test for Liver Function; Rattus; Recording of previous events; Rodent Model; Stimulus; Stress; Structure; Symptoms; Telemetry; Testing; Therapeutic Intervention; Veterans; associated symptom; base; 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) 归来后，退伍军人经历了一系列症状， 指定为海湾战争病（​​GWI），不能与单一疾病相关。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，以及 GWI 的一个更隐蔽的方面是它是一种慢性的、并且是慢性的。 事实上，诊断患有 GWI 的退伍军人人数在退役后持续增加。 尽管与 GWI 相关的无数症状的机制。 仍有待阐明，一些研究已确定 GWI 退伍军人表现出过度的免疫能力 对组合生理压力源的反应，与其他研究一起支持这样的概念： 神经炎症是 GWI 病因和进展的关键组成部分。 在之前的资助期间，我们开发了一种 GWI 啮齿动物模型，其中对大鼠进行了管理 乙酰胆碱酯酶 (AChE) 抑制剂溴化吡斯的明 (PB) 单独使用或联合使用 我们正在进行的研究表明，PB 和 RRS 会引起重复约束应激 (RRS) 的改变。 也许更重要的是，我们的心血管、神经内分泌、神经免疫和行为测量。 初步研究表明，脂多糖加剧了这些 PB+RRS 诱导的改变 (LPS) 或急性暴露于异质的社会压力源。 基线差异、既往 PB 病史和压力可能会使 GWI 退伍军人容易夸大其词 令人惊讶的是，在 GW 部署后对免疫挑战或压力生活经历的反应。 相对较少的研究直接检验了这一假设以确定潜在的机制 导致接触 PB 后对压力或免疫挑战的反应加剧。 该项目的目标是直接检验我们的总体假设，即免疫挑战和压力 刺激会导致神经免疫、神经化学、心血管和行为缺陷加剧 在海湾战争疾病的动物模型中暴露于胆碱酯酶抑制作用，这一假设将得到检验。 为了实现以下目标： • 目标 1 将检查免疫或压力挑战是否会导致神经免疫反应增强 PB+RRS大鼠 • 目标 2 将确定 LPS 或暴露的社会压力是否会增加心血管并发症 PB+RRS 大鼠中增强。 • 目标 3 将确定海马和前额皮质的表现是否依赖 LPS 管理或急性社会压力会对行为产生不利影响。 这些研究的成功完成将证明 PB 治疗与压力相结合会引起 大脑和身体反应的根本改变在免疫和免疫后可能会更加明显 社会压力挑战，这与 GWI 的进步性质高度一致 最重要的是，这些研究将确定可进行治疗干预的位点。 很快在我们的模型中进行了测试，并应用于退伍军人的 GWI 治疗。