Role Of Neuropeptides And Biogenic Amines In Stress and Brain Inflammation

神经肽和生物胺在压力和脑炎症中的作用

• 批准号: 7594528
• 负责人: JUAN M SAAVEDRA
• 金额: $ 226.35万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594528
• 关键词: AGTR2 gene; Acute; Adipose tissue; Adrenal Cortex Hormones; Adrenal Glands; Affect; Agonist; Aldosterone; Alzheimer' s Disease; Angiotensin II; Angiotensin II Receptor; Animal Model; Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Benzodiazepines; Binding; Biogenic Amines; Biological Preservation; Blood Pressure; Brain; Brain Diseases; Brain Ischemia; CRH gene; Cerebral cortex; Characteristics; Chronic; Class; Clinical; Clinical Protocols; Condition; Corticotropin; Corticotropin-Releasing Hormone; Development; Disease; Disease Progression; Encephalitis; Equilibrium; Estrogens; Fright; Gastric ulcer; Genetic Transcription; Glucocorticoids; Goals; Heart; High Blood Pressure; Hormonal; Hormones; Human; Human Volunteers; Hypertension; Hypothalamic structure; Immune response; Inbred SHR Rats; Inflammation; Inflammatory; Inflammatory Response; Ischemia; Kidney; Laboratories; Laboratory Study; Lead; Length; Life; Ligands; Limbic System; Lipopolysaccharides; Longevity; Mental Depression; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Nerve Degeneration; Neuropeptides; Organ; PPAR gamma; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pituitary Gland; Prevention approach; Prevention therapy; Preventive; Process; Production; Property; Protocols documentation; Rattus; Receptor Activation; Regulation; Renin-Angiotensin System; Reporting; Rodent; Role; Stimulus; Stress; Stroke; System; Testing; Therapeutic; Therapeutic Effect; Thinking; Time; Translating; Treatment Efficacy; Tyrosine 3-Monooxygenase; Undifferentiated; Vascular Dementia; Vasopressins; Week; adiponectin; base; biological adaptation to stress; cerebrovascular; diabetic; experience; hypothalamic-pituitary-adrenal axis; improved; in vivo; insulin sensitivity; interest; monocyte; multitask; neuropsychiatry; novel; novel strategies; novel therapeutics; paraventricular nucleus; pre-clinical; prevent; receptor; receptor expression; receptor upregulation; research study; response; response to injury; restraint; stress related disorder

Our laboratory studies the central mechanisms leading to anxiety, depression, stress-related illnesses and inflammatory diseases of the brain, with the goal to develop novel therapeutic strategies for these diseases. We initially found that the hormone and brain modulator Angiotensin II (Ang II), the active principle of the Renin-Angiotensin System (RAS), is a major factor in the regulation of the stress response, and that excess Ang II AT1 receptor stimulation participates in the development of anxiety and stress-related disorders, the vulnerability to brain ischemia and cerebrovascular inflammation (6, 7, 8). For these reasons, our current focus is on the functions of brain Ang II and on the therapeutic effects of Ang II AT1 receptor blockers (ARBs). Ang II participates in stress by regulating the hypothalamic-pituitary-adrenal (HPA) axis activating the production and release of CRH in the paraventricular nucleus, the secretion of vasopressin, and the central and peripheral sympathetic activity (1, 2). Excess AT1 receptor stimulation translates into excessive HPA axis and sympathetic activity during stress. Our laboratory has earlier demonstrated that pretreatment with a peripheral and central ARB completely prevents the hormonal and sympathoadrenal response to isolation stress and the production of stress-induced gastric ulcers in the rat during cold-restraint, new findings with important clinical implications. We now report that the influence of ARBs during stress is not confined to hypothalamic mechanisms. We found that AT1 receptor blockade has an anxiolytic effect, and prevents the stress-induced decrease in CRH1 and benzodiazepine binding in the cerebral cortex during isolation. Thus, central inhibition of AT1 receptors counteracts the stimulation not only of the hypothalamic CRF system but of the cortical CRF system as well (5). Preservation of normal benzodiazepine binding during stress can be interpreted as protection of the cortical GABA-A system leading to decreased anxiety during stress. We are continuing our studies on the effects of life-long ARB administration on the life span of the stress-sensitive Spontaneously Hypertensive Rats (SHR). ARBs substantially prolonged the life span of SHR, protecting the brain, heart and kidney from hypertension-related ischemia and inflammation. These compounds had a life-long anti-stress effect, with decreased sympathetic and HPA axis activity during isolation, and decreased anxiety during the whole length of the treatment (72 weeks). This indicates end-organ protection, anti-stress and anti-anxiety effects of ARBs, and reveals that the animals do not adapt to the beneficial effects of these compounds. Studies on the role of AT2 receptors reveal that these receptors regulate both the central sympathetic and the peripheral adrenomedullary activities, through the control of transcription of tyrosine hydroxylase. These findings indicate that AT2 receptors participate in the regulation of the central sympathetic and adrenomedullary response to stress. In AT2 -/- mice, the brain AT1 receptors are upregulated, suggesting a mutual influence of AT2 and AT1 receptor activation in AT1 and AT2 receptor expression. We initiated studies to determine the effect of ARBs on inflammatory stress. Administration of the bacterial endothoxin lipopolysaccharide (LPS) produces a characteristic stress response, with stimulation of aldosterone synthesis and release from the adrenal gland, and excess expression of AT1 receptors in the paraventricular nucleus of the hypothalamus. ARBs prevent the aldosterone response to LPS, without significantly affecting the HPA axis activity, because the release of ACTH and glucocorticoids is unaffected. These results demonstrate that while ARBs have general anti-stress effects, the regulation of the HPA axis depends on the type of stress. In the case of inflammatory stress, ARBs do not prevent the HPA axis response to inflammation. Protection of the anti-inflammatory corticoid response is a beneficial effect. Our preclinical experiments in rodents suggested the possibility to test the effects of ARBs in humans. We have recently proposed the first clinical protocol to evaluate the effects of AT1 receptor antagonists in the fear-startle response in human volunteers, and the protocol will start momentarily. The goal is to determine if AT1 receptor antagonists are effective in reducing anxiety and stress in humans. We have earlier discovered, using SHRs, that ARBs reverse the chronic cerebrovascular inflammation characteristic of hypertension, leading to reversal of cerebrovascular remodeling and vulnerability to brain ischemia, effects dependent on the regulation of the cerebrovascular RAS and not of the circulating, hormonal RAS (11) , and unrelated to the effects of ARBs on blood pressure. These findings indicated that ARBs may also prevent or reverse inflammatory conditions of the brain unrelated to hypertension. We chose a model of acute inflammation, the administration of lipopolysaccharide (LPS). We found that AT1 receptor blockade prevented the complete peripheral and brain inflammatory response to LPS when injected in vivo to rats. We also found a significant reduction of the LPS response in cultured undifferentiated human monocytes. These findings demonstrate a role of Angiotensin II in the innate immune response, and reveal that AT1 receptor antagonists are effective anti-inflammatory compounds. Because circulating human monocytes do not express AT1 receptors, our finding indicate AT1 receptor-independent effects of ARBs. Understanding these non-Ang II effects may provide additional information for the development of novel anti-inflammatory compounds. Additional experiments demonstrate that there is a complete Renin-Angiotensin System in adipose tissue. Treatment with AT1 antagonists improves insulin sensitivity and increases the levels of adiponectin, a hormone released by adipose tissue and exerting anti-inflammatory effects in the vasculature (12). Our findings that ARBs stimulate the function of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) reveal additional non-Ang II effects of these compounds and are important to clarify the molecular mechanisms of the anti-diabetic properties of ARBs. Activation of AT2 receptors has been proposed to balance AT1 receptor stimulation and to exert anti-inflammatory effects. Our findings that estrogens dramatically up regulate AT2 receptor expression indicate a possible participation of AT2 receptor activation on the anti-inflammatory effects of estrogen. Our results indicate that ARBs may be considered as a novel class of multitasking anti-stress, anti-anxiety, anti-inflammatory medications in the treatment of brain disorders. Because these compounds, widely used to treat high blood pressure in humans, are safe and are devoid of addictive properties, development of new compounds of this class may result in medications of great therapeutic potential. The role of AT2 receptors remains an open question. We continue our experiments to clarify: 1) the central regulation of the stress response with emphasis on hypothalamic and supra-hypothalamic mechanisms and the role of Ang II, the factors leading to enhanced vulnerability to stress, and the mechanisms and limitations of the anti-stress effects of ARBs and AT2 related compounds; and 2) the role and mechanism of the pro-inflammatory effect of Ang II in the brain and the mechanisms of Ang II related and unrelated anti-inflammatory effects of ARBs, and the role of AT2 receptors in brain inflammation.

我们的实验室研究导致焦虑，抑郁，与压力有关的疾病和大脑炎症性疾病的中心机制，其目标是为这些疾病开发新的治疗策略。我们最初发现，激素和脑调节剂血管紧张素II（ANG II）是肾素 - 血管紧张素系统（RAS）的活性原理，是调节压力反应的主要因素，而过量的ANG II AT1受体刺激参与了焦虑和压力疾病的发展，脑部和脑部疾病的发育能力和脑部脑疾病和刺激性为8）。由于这些原因，我们目前的重点是脑ANG II的功能以及ANG II AT1受体阻滞剂（ARB）的治疗作用。 ANG II通过调节下丘脑 - 垂体 - 肾上腺（HPA）轴来激活CRH的产生和释放，该轴是在旁脑核中激活CRH的产生和释放，加压素的分泌以及中枢和周围交感神经活性（1，2）。过量的AT1受体刺激转化为过度HPA轴和压力期间的交感神经活动。我们的实验室早些时候证明，对周围和中央ARB进行预处理，完全防止了对分离应激的激素和交感肾上腺反应，以及在冷我的大鼠冷抑制作用期间的胁迫诱导的胃溃疡的产生，具有重要的临床意义。现在，我们报告说，压力期间ARB的影响不仅限于下丘脑机制。我们发现AT1受体阻滞具有抗焦虑作用，并防止了分离过程中大脑皮层中CRH1和苯二氮卓类结合的应力诱导的降低。因此，对AT1受体的中心抑制不仅可以抵消下丘脑CRF系统的刺激，而且还抵消了皮质CRF系统的刺激（5）。在应激过程中保留正常的苯二氮卓类结合可以解释为对皮质GABA-A系统的保护，从而导致压力下焦虑降低。 我们正在继续研究终身ARB给药对压力敏感的自发性高血压大鼠（SHR）的寿命的影响。 ARB大大延长了SHR的寿命，保护大脑，心脏和肾脏免受与高血压相关的缺血和炎症的影响。这些化合物具有终生的抗压力作用，在分离过程中交感神经和HPA轴活动降低，并且在整个治疗期间（72周）期间焦虑降低。这表明ARB的最终器官保护，抗压力和抗焦虑作用，并揭示了动物不适应这些化合物的有益作用。 关于AT2受体作用的研究表明，这些受体通过控制酪氨酸羟化酶的转录来调节中心交感神经和周围肾上腺肾上腺肾上腺肾上腺素的活性。这些发现表明，AT2受体参与对压力的中心交感神经和肾上腺囊肿反应的调节。在AT2 - / - 小鼠中，大脑AT1受体被上调，表明AT2和AT1受体在AT1和AT2受体表达中产生了相互影响。 我们开始研究以确定ARB对炎症应激的影响。细菌内毒素脂多糖（LPS）的施用产生特征性的应激反应，并刺激醛固酮合成并从肾上腺中释放，并且在下丘脑的副脑核中AT1受体的过量表达。 ARB可以防止醛固酮对LP的反应，而不会显着影响HPA轴活动，因为ACTH和糖皮质激素的释放不受影响。这些结果表明，尽管ARB具有一般的抗压力作用，但HPA轴的调节取决于应力的类型。在炎症应激的情况下，ARB不能阻止HPA轴对炎症的反应。保护抗炎性皮质激素反应是一种有益的作用。我们在啮齿动物中进行的临床前实验表明，有可能测试ARB在人类中的影响。我们最近提出了第一个评估AT1受体拮抗剂在人类志愿者中的恐惧反应中的影响的临床方案，该方案将暂时开始。目的是确定AT1受体拮抗剂是否有效减少人类的焦虑和压力。 我们先前发现，使用SHR，ARB逆转了高血压的慢性脑血管炎症特征，导致脑血管骨血管重塑和脑部缺血的脆弱性的逆转，取决于脑血管ras的调节，而不是循环，荷尔蒙Ras（11）和不及时的疾病和不及时的疾病。这些发现表明，ARB还可以预防与高血压无关的大脑的炎症状况。我们选择了急性炎症模型，脂多糖（LPS）的给药。我们发现，当体内注入大鼠时，AT1受体阻滞阻止了对LP的完全外周和脑炎症反应。我们还发现，在未分化的人类单核细胞中，LPS反应显着降低。这些发现表明了血管紧张素II在先天免疫反应中的作用，并揭示了AT1受体拮抗剂是有效的抗炎化合物。因为循环的人单核细胞不表达AT1受体，所以我们的发现表明AT1受体独立的作用。了解这些非Ang II效应可能会为开发新型抗炎化合物的发展提供其他信息。 其他实验表明，脂肪组织中有一个完整的肾素 - 血管紧张素系统。用AT1拮抗剂治疗可提高胰岛素敏感性并增加脂联素的水平，脂肪组织释放的激素并在脉管系统中发挥抗炎作用（12）。我们的发现，ARB刺激过氧化物酶体增殖物激活的受体伽马（PPAR-GAMMA）的功能揭示了这些化合物的其他非Ang II效应，并且对于阐明ARB的抗糖尿病性质的分子机制非常重要。 已经提出了AT2受体的激活来平衡AT1受体刺激并发挥抗炎作用。我们的发现显着提高了AT2受体表达，表明AT2受体激活对雌激素的抗炎作用的可能参与。 我们的结果表明，ARB可以被视为一类新型的多任务反应，抗焦虑，抗炎药在治疗脑部疾病时。由于这些化合物（广泛用于治疗人类的高血压）是安全的并且没有上瘾的特性，因此该类别的新化合物的发展可能会导致具有巨大治疗潜力的药物。 AT2受体的作用仍然是一个悬而未决的问题。 我们继续进行实验以澄清：1）压力反应的中心调节，重点是下丘脑和上丘脑上丘脑机制以及ANG II的作用，这些因素导致了压力脆弱性，以及ARBS和ARBS和AT2相关化合物的抗压力效应的机制和局限性； 2）ANG II在大脑中的促炎作用的作用和机制以及ANG II相关和无关的ARB的抗炎作用的机制，以及AT2受体在脑部炎症中的作用。