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: 8443171
• 负责人: GEORGINA CANO
• 金额: $ 7.61万
• 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/8443171
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Insomnia, the most prevalent sleep disorder, is induced by stress. Current pharmacologic treatments are unspecific and cause undesirable side-effects. The aim of this proposal is to test an angiotensin II antagonist, known to exert a potent anti-stress effect, in ameliorating the sleep disturbances observed in a rat model of insomnia.

描述（由申请人提供）：失眠是正常人群中最普遍的睡眠障碍，它也是几种精神疾病的基本特征。失眠与白天嗜睡，疲劳，表现受损和记忆力受损，认知和精神病缺陷以及焦虑和烦躁的增加有关。尽管对健康和生产力产生了有害影响，但对这种睡眠障碍的基本神经机制知之甚少。目前对失眠症的治疗方法是症状的，而不是这些症状构成的病理生理改变，这些治疗方法与不良的副作用以及滥用和依赖性的高风险有关。此外，当前治疗可大大减少REM睡眠，并且不会恢复正常的睡眠。因此，开发更具体的药物治疗失眠症是重中之重。失眠是由诱发的个体的压力性生活事件引起的，一般而言，失眠症显示神经内分泌和交感肾上腺活性增加。血管紧张素II（AngII）是一个信号分子，在外围和中心均发现。外围Angii以其在心血管调节中的作用而闻名，并且阻断Angii信号传导的药物经常用于治疗心血管疾病。最近的工作表明，脑Angii参与了压力反应的调节。中央ANGII和ANGII AT1受体表达在压力期间增加，进而激活交感神经和神经内分泌系统。这些效果可以通过施用Angii拮抗剂的给药，也可以通过中央Angii给药模仿。在参与应力反应的大脑区域已经鉴定出血管肌受体，这表明Angii效应是通过直接激活这些神经元组发生的。新兴的证据表明，在心理情绪压力期间，脑血管病主要参与心血管唤醒的调节。我们开发了一种大鼠大鼠失眠的大鼠模型，并表征了在失眠期间激活的神经解剖回路。我们发现，由于情绪压力，昼夜节律驱动器和稳态驱动器驱动的促进睡眠区域的同时激活了边缘和唤醒（唤醒）系统。因此，在失眠期间，边缘系统（参与情绪处理）被激活，然后激活一部分唤醒系统，后来激活了大脑皮层，从而引起这种疾病中观察到的睡眠干扰。失眠中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，施用ANGII AT1拮抗剂将抑制这些边缘组，然后抑制下游电路（唤醒系统和皮层），从而减弱了压力对睡眠的影响并有助于恢复正常的睡眠。该提案的目的是通过在我们的压力引起的失眠模型中测试Angii拮抗剂Candesartan来评估这一假设，这对于对具有潜在抗刺激性的化合物的第一频繁筛选很有用。我们的目标是找到一种用于恢复自然睡眠的失眠症的药理学治疗方法，并通过对更具体的大脑靶标作用来最大程度地减少副作用。 公共卫生相关性：失眠是最普遍的睡眠障碍，是由压力引起的。当前的药理学治疗是非特异性的，并且会导致不良的副作用。该建议的目的是测试血管紧张素II拮抗剂，已知会发挥有效的抗压力作用，以改善在失眠大鼠模型中观察到的睡眠障碍。