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

基本信息

项目摘要

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、压力相关疾病和大脑炎症性疾病的核心机制,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大脑调节剂血管紧张素 II (Ang II) 是肾素-血管紧张素系统 (RAS) 的活性成分,是调节应激反应的主要因素,过度的 Ang II AT1 受体刺激参与了应激反应的调节。在焦虑和压力相关疾病的发展过程中,容易发生脑缺血和脑血管炎症 (6,7,8)。由于这些原因,我们目前的重点是大脑 Ang II 的功能和 Ang II AT1 受体阻滞剂 (ARB) 的治疗效果。 Ang II 通过调节下丘脑-垂体-肾上腺 (HPA) 轴激活室旁核中 CRH 的产生和释放、加压素的分泌以及中枢和外周交感神经活动来参与应激 (1, 2)。应激期间过度的 AT1 受体刺激会转化为过度的 HPA 轴和交感神经活动。我们的实验室早些时候已经证明,用外周和中枢 ARB 进行预处理可以完全防止大鼠在寒冷限制期间对隔离应激的激素和交感肾上腺反应以及应激诱发的胃溃疡的产生,这一新发现具有重要的临床意义。我们现在报告说,ARB 在应激期间的影响不仅限于下丘脑机制。我们发现 AT1 受体阻断具有抗焦虑作用,并可防止隔离期间应激引起的大脑皮层 CRH1 和苯二氮卓结合的减少。因此,AT1 受体的中枢抑制不仅会抵消下丘脑 CRF 系统的刺激,还会抵消皮质 CRF 系统的刺激 (5)。在压力期间保持正常的苯二氮卓结合可以解释为保护皮质 GABA-A 系统,从而减少压力期间的焦虑。 我们正在继续研究终生 ARB 给药对应激敏感的自发性高血压大鼠 (SHR) 寿命的影响。 ARB 显着延长了 SHR 的寿命,保护大脑、心脏和肾脏免受高血压相关的缺血和炎症的影响。这些化合物具有终生抗应激作用,在隔离期间降低交感神经和 HPA 轴活性,并在整个治疗期间(72 周)减少焦虑。这表明 ARB 具有终末器官保护、抗应激和抗焦虑作用,并揭示动物不适应这些化合物的有益作用。 对 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枢交感神经和外周肾上腺髓质活动。这些发现表明 AT2 受体参与调节中枢交感神经和肾上腺髓质对应激的反应。在 AT2 -/- 小鼠中,大脑 AT1 受体上调,表明 AT2 和 AT1 受体激活对 AT1 和 AT2 受体表达的相互影响。 我们启动了研究以确定 ARB 对炎症应激的影响。细菌内毒素脂多糖 (LPS) 的施用会产生特有的应激反应,刺激醛固酮的合成和肾上腺的释放,以及下丘脑室旁核中 AT1 受体的过量表达。 ARB 可阻止醛固酮对 LPS 的反应,但不会显着影响 HPA 轴活性,因为 ACTH 和糖皮质激素的释放不受影响。这些结果表明,虽然 ARB 具有一般的抗应激作用,但 HPA 轴的调节取决于应激的类型。在炎症应激的情况下,ARB 不会阻止 HPA 轴对炎症的反应。保护抗炎皮质激素反应是一种有益的作用。我们在啮齿类动物中进行的临床前实验表明有可能测试 ARB 对人类的影响。我们最近提出了第一个临床方案来评估 AT1 受体拮抗剂对人类志愿者恐惧惊吓反应的影响,该方案将立即启动。目标是确定 AT1 受体拮抗剂是否能有效减轻人类的焦虑和压力。 我们早些时候发现,使用 SHR,ARB 可以逆转高血压的慢性脑血管炎症特征,从而逆转脑血管重塑和脑缺血的脆弱性,其作用取决于脑血管 RAS 的调节,而不是循环激素 RAS 的调节(11 ),与 ARB 对血压的影响无关。这些发现表明,ARB 还可以预防或逆转与高血压无关的大脑炎症状况。我们选择了急性炎症模型,即脂多糖(LPS)的施用。我们发现,当将 LPS 注射到大鼠体内时,AT1 受体阻断可以完全阻止外周和大脑对 LPS 的炎症反应。我们还发现培养的未分化人类单核细胞的 LPS 反应显着降低。这些发现证明了血管紧张素 II 在先天免疫反应中的作用,并揭示 AT1 受体拮抗剂是有效的抗炎化合物。由于循环人类单核细胞不表达 AT1 受体,我们的发现表明 ARB 具有不依赖于 AT1 受体的作用。了解这些非 Ang II 效应可能为新型抗炎化合物的开发提供更多信息。 其他实验表明脂肪组织中存在完整的肾素-血管紧张素系统。 AT1 拮抗剂治疗可改善胰岛素敏感性并增加脂联素的水平,脂联素是一种由脂肪组织释放的激素,在脉管系统中发挥抗炎作用 (12)。我们发现 ARB 刺激过氧化物酶体增殖物激活受体 γ (PPAR-γ) 的功能,揭示了这些化合物的额外非血管紧张素 II 作用,对于阐明 ARB 抗糖尿病特性的分子机制非常重要。 AT2 受体的激活被认为可以平衡 AT1 受体的刺激并发挥抗炎作用。我们发现雌激素显着上调 AT2 受体表达,表明 AT2 受体激活可能参与雌激素的抗炎作用。 我们的结果表明,ARB 可能被认为是治疗脑部疾病的一类新型多任务抗压力、抗焦虑、抗炎药物。由于这些广泛用于治疗人类高血压的化合物是安全的并且没有成瘾性,因此开发此类新化合物可能会产生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阐明:1)应激反应的中枢调节,重点是下丘脑和上下丘脑机制以及Ang II的作用,导致应激脆弱性增强的因素,以及抗应激的机制和局限性。 ARB 和 AT2 相关化合物的应激作用; 2)Ang II在脑内促炎作用的作用和机制,Ang II相关和不相关的ARB抗炎作用机制,以及AT2受体在脑炎症中的作用。

项目成果

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JUAN M SAAVEDRA其他文献

JUAN M SAAVEDRA的其他文献

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{{ truncateString('JUAN M SAAVEDRA', 18)}}的其他基金

Brain pathophysiology in SARS-CoV-2 disease
SARS-CoV-2 疾病的脑病理生理学
  • 批准号:
    10317394
  • 财政年份:
    2021
  • 资助金额:
    $ 226.35万
  • 项目类别:
Brain pathophysiology in SARS-CoV-2 disease
SARS-CoV-2 疾病的脑病理生理学
  • 批准号:
    10617754
  • 财政年份:
    2021
  • 资助金额:
    $ 226.35万
  • 项目类别:
Brain pathophysiology in SARS-CoV-2 disease
SARS-CoV-2 疾病的脑病理生理学
  • 批准号:
    10434951
  • 财政年份:
    2021
  • 资助金额:
    $ 226.35万
  • 项目类别:
Mechanistic studies on stress, brain inflammation and neuroprotection
压力、脑炎症和神经保护的机制研究
  • 批准号:
    8342121
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
Role Of Neuropeptides And Biogenic Amines In Stress And
神经肽和生物胺在压力和压力中的作用
  • 批准号:
    6507482
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
Role Of Neuropeptides And Biogenic Amines In Stress And
神经肽和生物胺在压力和压力中的作用
  • 批准号:
    6824171
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
Mechanistic studies on stress, brain inflammation and neuroprotection
压力、脑炎症和神经保护的机制研究
  • 批准号:
    8745697
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
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:
    7969333
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
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:
    7735135
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:
ROLE OF NEUROPEPTIDES AND BIOGENIC AMINES IN STRESS AND BRAIN ISCHEMIA
神经肽和生物胺在压力和脑缺血中的作用
  • 批准号:
    6290596
  • 财政年份:
  • 资助金额:
    $ 226.35万
  • 项目类别:

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