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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

批准号：
7735135
负责人：
JUAN M SAAVEDRA
金额：
$ 230.13万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/7735135
关键词：
AGTR2 gene Acute Adrenal Cortex Hormones Adrenal Glands Agonist Aldosterone Angiotensin II Angiotensin II Receptor Angiotensin Receptor Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Anxiety Area Binding Biogenic Amines Biological Psychiatry Biotin Birth Brain Brain Diseases CD14 Antigen CD14 gene CGP-42112 Cerebrum Characteristics Chronic Class Clinical Protocols Collaborations Complex Condition Corticosterone Corticotropin Corticotropin-Releasing Hormone Coupling Cultured Cells Development Development, Other Dinoprostone Disease Dissection Encephalitis Endothelial Cells Endothelium Endotoxins Equilibrium FOS gene Fright Gene Deletion Gene Expression Gene Silencing Genes Genetic Models Genetic Transcription Goals High Blood Pressure Hippocampus (Brain)Hormones Human Human Volunteers Hypertension Hypothalamic structure Immune Immune response Immunohistochemistry In Vitro Inflammation Inflammatory Inflammatory Response Label Lead Limbic System Lipopolysaccharides Localized Mediating Mental Depression Microglia Mineralocorticoids Mus NADP NF-kappa B National Institute of Mental Health Nerve Degeneration Neurodegenerative Disorders Neurons Neuropeptides Nitric Oxide Nitric Oxide Synthase Numbers Oxidases Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Pituitary Gland Play Post-Traumatic Stress Disorders Prevention approach Production Property Proteins Proteomics Purpose Rattus Reaction Reactive Oxygen Species Receptor Gene Regulation Reporting Research Rodent Rodent Model Role Signal Transduction Site Spleen Stimulus Streptavidin Stress System Techniques Therapeutic Time Transcriptional Activation Transfection Treatment Efficacy Tyrosine 3-Monooxygenase Up-Regulation Work adiponectin base candesartan cell type cerebrovascular cyclooxygenase 2 cytokine familial hypertension hypothalamic-pituitary-adrenal axis in vivo laser capture microdissection locus ceruleus structure macrophage molecular recognition monocyte mouse model multitask neuropsychiatry novel novel strategies novel therapeutics paraventricular nucleus prevent protein protein interaction receptor research study response response to injury transcription factor

项目摘要

Brain inflammation. In previous work, we had found that sustained in vivo AT1 receptor blockade with the ARB candesartan reversed, in a rat model of genetic hypertension, the cerebrovascular inflammation which is characteristic of hypertension in both rodents and humans. We asked the question whether ARBs could reduce other types of brain inflammation. During FY 2008, we focused on the effect of ARBs on the rat innate immune response, produced by systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). We found that ARBs limited the peripheral and brain inflammatory responses to systemic immune challenge in the rat. In vivo, ARBs reduced the LPS-induced inflammatory reaction in rodent spleen, adrenal gland, pituitary gland, and in multiple brain areas including the hypothalamus, olfactory system, hippocampus and cortex. Anti-inflammatory effects of ARBs were more pronounced in areas expressing large numbers of neuronal AT1 receptors. In addition, ARBs reduced the LPS-induced increase of the pro-inflammatory mineralocorticoid hormone aldosterone and enhanced the production of the anti-inflammatory hormone adiponectin. Moreover, ARBs rapidly reduced, in vitro, the LPS-induced pro-inflammatory gene expression and secretion of pro-inflammatory cytokines in cultured human monocytes. We next focused on the elucidation of the mechanisms of the anti-inflammatory effects of ARBs, and we asked the question which of the major mechanisms of inflammation stimulated by LPS were reduced or eliminated by ARB administration. We found that ARBs reduced, in vivo, the LPS-induced production of multiple pro-inflammatory factors, including reactive oxygen species, nitric oxide and prostaglandin E2. This implicates mechanisms involving Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase, cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS) and transcription factors such as NF-kappaB. We found similar ARB effects, in vitro, in cultured human circulating monocytes. A repeated finding after ARB administration was the decrease in the constitutive and in the LPS-induced expression of the LPS receptor CD14. We hypothesize that interference with the LPS molecular recognition complex may explain part of the anti-inflammatory effects of ARBs. We are now focusing on the further clarification of the mechanisms of action of ARBs. We use a mouse model of AT1 receptor gene-deletion, to determine the effect of LPS when AT1 receptors are not expressed from birth. Cerebral endothelium plays a crucial role in the propagation of inflammatory signals throughout the brain and is critical for activation of specific groups of neurons involved in central response to systemic inflammation. We use cultures of cerebral endothelial cells and isolated microglia to study the relationship between LPS and AT1 receptors, to determine cellular colocalization and direct protein-protein interactions. Studies include gene transfections and gene silencing techniques in phenotype rescue studies and to identify critical components mediating the effect of ARBs in particular cell types. These experiments will further clarify the mechanisms of the anti-inflammatory effects of ARBs. In previous work, we have reported that CGP42112, an agonist of a second type of Ang II receptors, the AT2 receptors, actively inhibits the LPS-induced inflammation in human monocytes. During FY 2008 we discovered that, in rodents, CGP42112 effectively decreases LPS-induced inflammation in vivo. The anti-inflammatory effects of CGP42112 could be the result of AT2 receptor stimulation and/or binding to a novel macrophage receptor that we have previously discovered and reported, localized to brain and circulating macrophages. This novel non-Angiotensin receptor has not yet been characterized. In collaboration with Drs. Markey, NIMH, we are attempting to identify proteins which bind to CGP42112 using biotin-labeled CGP42112 and isolation by streptavidin coupling, and by laser capture microdissection, immunohistochemistry and proteomics. In other studies we will characterize the mechanisms of CGP42112 novel anti-inflammatory effects using AT2 gene-deleted mice and human circulating monocytes. Stress. We previously demonstrated that orally administered ARBs limited the HPA axis, sympathetic and cortical responses to isolation stress, and that these compounds reduced anxiety in rodents. On this basis, we previously proposed the first clinical protocol to evaluate the effects of AT1 receptor antagonists in the fear-startle response in human volunteers, with the goal to determine if AT1 receptor antagonists are effective in reducing anxiety and stress in humans. During FY 2008, we further explored the anti-stress effects of ARBs in response to immune challenge. We now find that ARBs limit the HPA axis response to the endotoxin lipopolysaccharide (LPS) in the adrenal gland, pituitary and hypothalamus. ARBs decreased the LPS-induced upregulation of the early transcription factor c-fos and microglial activation in the paraventricular nucleus. While eliminating the LPS-induced up-regulation of the hormone aldosterone, ARBs do not decrease LPS-induced ACTH and corticosterone responses, demonstrating that ARBs do not limit the anti-inflammatory effects of LPS-induced corticosteroid release. We found that the effect of ARBs on the HPA axis depend on the type of stress. During isolation stress, ARBs prevent HPA axis activation, but they do not prevent the HPA axis response to inflammation. We have also found that ARBs prevent the stress-induced increase in brain sympathetic activity by suppressing the stress-induced tyrosine hydroxylase gene transcription in the rat locus coeruleus. Our experiments are now focused on the elucidation of the mechanisms of the ARB control of tyrosine hydroxylase transcription in the locus coeruleus, the regulation of corticotrophin-releasing factor in the paraventricular nucleus, and the determination of additional brain sites involved on the anti-stress effects of ARBs. To this end we combine selective dissection techniques, gene microarray and proteomic studies. In conclusion, we demonstrated during the FY 2008 that ARBs may be considered as a novel class of multitasking anti-stress, anti-anxiety, anti-inflammatory medications in the treatment of brain disorders. They are already widely used to treat high blood pressure in humans and are safe and devoid of addictive properties, Elucidation of their mechanisms of action may lead to the development of other compounds of great therapeutic potential.

大脑炎症。在之前的工作中，我们发现，在遗传性高血压大鼠模型中，持续的体内AT1受体阻断与ARB坎地沙坦逆转了脑血管炎症，这是啮齿动物和人类高血压的特征。我们提出的问题是，arb是否可以减少其他类型的脑部炎症。在2008财政年度，我们重点研究了ARBs对大鼠先天免疫反应的影响，该反应是由细菌内毒素脂多糖（LPS）系统管理产生的。我们发现ARBs限制了大鼠对全身免疫挑战的外周和脑炎症反应。在体内，ARBs降低了lps诱导的鼠脾、肾上腺、垂体以及下丘脑、嗅觉系统、海马和皮质等多个脑区炎症反应。ARBs的抗炎作用在表达大量AT1受体的神经元区域更为明显。此外，ARBs降低了lps诱导的促炎矿物皮质激素醛固酮的升高，并增强了抗炎激素脂联素的产生。此外，ARBs在体外可迅速降低lps诱导的促炎基因表达和促炎细胞因子的分泌。接下来，我们重点阐明了ARB抗炎作用的机制，并提出了由LPS刺激的炎症的哪些主要机制被ARB减少或消除的问题。我们发现，在体内，ARBs减少了lps诱导的多种促炎因子的产生，包括活性氧、一氧化氮和前列腺素E2。这暗示了涉及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶、环氧化酶-2 （COX-2）、一氧化氮合酶（NOS）和转录因子如nf - κ b的机制。我们在体外培养的人类循环单核细胞中发现了类似的ARB效应。ARB给药后的重复发现是LPS诱导的LPS受体CD14的组成和表达减少。我们假设干扰LPS分子识别复合体可以部分解释arb的抗炎作用。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The future of Latin American science.

拉丁美洲科学的未来。

DOI：
10.1023/a:1021853625299
发表时间：
2002
期刊：
Cellular and molecular neurobiology
影响因子：
4
作者：
Saavedra,JuanM
通讯作者：
Saavedra,JuanM

Increased AT(1) receptor expression and mRNA in kidney glomeruli of AT(2) receptor gene-disrupted mice.

AT(2) 受体基因破坏小鼠肾小球中 AT(1) 受体表达和 mRNA 增加。

DOI：
10.1152/ajprenal.2001.280.1.f71
发表时间：
2001
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Saavedra,JM;Hauser,W;Ciuffo,G;Egidy,G;Hoe,KL;Johren,O;Sembonmatsu,T;Inagami,T;Armando,I
通讯作者：
Armando,I

Intracisternal administration of Angiotensin II AT1 receptor antisense oligodeoxynucleotides protects against cerebral ischemia in spontaneously hypertensive rats.

血管紧张素 II AT1 受体反义寡脱氧核苷酸的脑池内给药可预防自发性高血压大鼠的脑缺血。