Effects of an angiotensin ll antagonist in a rat model of insomnia

血管紧张素II拮抗剂对失眠大鼠模型的影响

• 批准号: 8536955
• 负责人: GEORGINA CANO
• 金额: $ 7.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-28 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536955
• 关键词: Adverse effects; Affect; Amygdaloid structure; Angiotensin II; Angiotensin II Receptor; Angiotensins; Antidepressive Agents; Anxiety; Area; Arousal; Attenuated; Benzodiazepines; Brain; Brain region; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cerebral cortex; Circadian Rhythms; Cognitive; Data; Dependence; Detection; Development; Disease; Drowsiness; Drug Regulations; Emotional; Emotional Stress; Event; Fatigue; Goals; Health; Individual; Lesion; Life; Limbic System; Mediating; Memory; Mental disorders; Modeling; Motor; Neurons; Neurosecretory Systems; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Process; Productivity; Property; Proteins; REM Sleep; Rattus; Regulation; Role; Safety; Sedation procedure; Signal Transduction; Signaling Molecule; Site; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Testing; Therapeutic; Work; biological adaptation to stress; high risk; improved; neuromechanism; psychosocial; receptor; receptor expression; response; screening; stress related disorder; stressor; tool; transcription factor

DESCRIPTION (provided by applicant): Insomnia is the most prevalent sleep disorder in the normal population and it is also a cardinal feature of several psychiatric disorders. Insomnia is associated with daytime sleepiness, fatigue, impaired performance and memory, cognitive and psychomotor deficits, and increased anxiety and irritability. Despite the deleterious effects on health and productivity, little is known about the basic neural mechanisms underlying this sleep disorder. Current treatments for insomnia target the symptoms instead of the pathophysiologic alterations that underlie those symptoms, and these treatments are associated with undesirable side effects as well as high risk for abuse and dependence. In addition, current treatments decrease REM sleep substantially and do not restore normal sleep. Therefore, the development of more specific pharmacotherapy for the treatment of insomnia is a top priority. Insomnia is triggered by stressful life events in predisposed individuals and, in general, insomniacs show increased neuroendocrine and sympathoadrenal activity. Angiotensin II (AngII) is a signaling molecule found both peripherally and centrally. Peripheral AngII is well known for its role in cardiovascular regulation, and drugs that block AngII signaling are frequently used to treat cardiovascular disease. Recent work suggests that brain AngII is involved in the regulation of stress responses. Central AngII and AngII AT1 receptor expression increase during stress and, in turn, activate both the sympathoadrenal and neuroendocrine systems. These effects can be blocked by administration of AngII antagonists or mimicked by central AngII administration. AngII receptors have been identified in brain regions involved in stress responses, suggesting that AngII effect occurs via direct activation of these neuronal groups. Emerging evidence suggest that brain AngII is primarily involved in the regulation of cardiovascular arousal during psychoemotional stress. We developed a rat model of stress-induced insomnia in rats and characterized the neuroanatomical circuitry activated during insomnia. We found that there is simultaneous activation of the sleep-promoting areas, driven by the circadian and homeostatic drives, and the limbic and arousal (wake) systems due to the emotional stress. Thus, during insomnia, the limbic system (involved in emotional processing) becomes activated and, in turn, activates part of the arousal system, which subsequently activates the cerebral cortex, causing the sleep disturbances observed in this disorder. The relevant limbic structures activated in insomnia express high levels of AngII AT1 receptors. Our hypothesis is that administration of an AngII AT1 antagonist will inhibit these limbic groups and subsequently the downstream circuitry (arousal system and cortex), attenuating the effects of stress on sleep and helping to recover normal sleep. The aim of this proposal is to assess this hypothesis by testing candesartan, an AngII antagonist, in our stress-induced insomnia model, which is useful for first-pass screening of compounds with potential anti-insomnia properties. Our goal is to find a pharmacologic treatment for insomnia that restores natural sleep and minimizes side-effects by acting on more specific brain targets.

描述（由申请人提供）：失眠是正常人群中最普遍的睡眠障碍，也是多种精神疾病的主要特征。失眠与白天嗜睡、疲劳、表现和记忆力受损、认知和精神运动缺陷以及焦虑和烦躁增加有关。尽管对健康和生产力产生有害影响，但人们对这种睡眠障碍背后的基本神经机制知之甚少。目前失眠的治疗针对的是症状，而不是这些症状背后的病理生理改变，这些治疗会带来不良副作用以及滥用和依赖的高风险。此外，目前的治疗大大减少快速眼动睡眠，并且不能恢复正常睡眠。因此，开发更有针对性的治疗失眠的药物疗法是当务之急。失眠是由易感个体的压力生活事件引发的，一般来说，失眠症患者表现出神经内分泌和交感肾上腺活动增加。血管紧张素 II (AngII) 是一种在外周和中枢均发现的信号分子。外周血管紧张素II因其在心血管调节中的作用而闻名，阻断血管紧张素II信号传导的药物经常用于治疗心血管疾病。最近的研究表明大脑 AngII 参与应激反应的调节。中枢 AngII 和 AngII AT1 受体表达在应激过程中增加，进而激活交感肾上腺和神经内分泌系统。这些作用可以通过施用 AngII 拮抗剂来阻断或通过中枢 AngII 施用来模拟。 AngII 受体已在参与应激反应的大脑区域中被发现，这表明 AngII 效应是通过直接激活这些神经元群而发生的。新的证据表明，大脑 AngII 主要参与心理情绪应激期间心血管唤醒的调节。我们开发了一种应激性失眠大鼠模型，并表征了失眠期间激活的神经解剖回路。我们发现，在昼夜节律和稳态驱动的驱动下，促进睡眠的区域以及由于情绪压力而导致的边缘系统和唤醒（唤醒）系统同时激活。因此，在失眠期间，边缘系统（参与情绪处理）被激活，进而激活部分唤醒系统，随后激活大脑皮层，导致在这种疾病中观察到的睡眠障碍。失眠时激活的相关边缘结构表达高水平的 AngII AT1 受体。我们的假设是，使用 AngII AT1 拮抗剂会抑制这些边缘系统，进而抑制下游回路（唤醒系统和皮质），从而减轻压力对睡眠的影响，帮助恢复正常睡眠。本提案的目的是通过在我们的压力诱导失眠模型中测试坎地沙坦（一种 AngII 拮抗剂）来评估这一假设，这对于首次筛选具有潜在抗失眠特性的化合物非常有用。我们的目标是找到一种治疗失眠的药物治疗方法，通过作用于更具体的大脑目标来恢复自然睡眠并最大限度地减少副作用。