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Mechanistic studies on stress, brain inflammation and neuroprotection

压力、脑炎症和神经保护的机制研究

基本信息

批准号：
8745697
负责人：
JUAN M SAAVEDRA
金额：
$ 49.47万
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/8745697
关键词：
Aging Aging-Related Process Agonist Alzheimer&apos s Disease Angiotensin II Animal Model Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Anxiety B-Lymphocytes Behavior Biological Psychiatry Blood - brain barrier anatomy Brain Brain Diseases Brain Ischemia Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cells Cerebrum Cessation of life Characteristics Consensus Diabetes Mellitus Dinoprostone Disease Encephalitis Endothelial Cells Endotoxins Enhancers Equilibrium Fibrosis Functional disorder Genetic Predisposition to Disease Glutamates Goals Growth Human Hypertension Infiltration Inflammation Inflammatory Knockout Mice Lead Lesion Light Lipopolysaccharides Longevity Mental Depression Metabolic Metabolic Diseases Microglia Modeling Mood Disorders NADP Names Nervous System Physiology Neurodegenerative Disorders Neuronal Injury Neurons Nitric Oxide Nuclear Oxidases Oxidation-Reduction PPAR gamma Pathologic Processes Peripheral Permeability Pharmacology Play Post-Traumatic Stress Disorders Pre-Clinical Model Production Protein Kinase Proteins Rattus Reactive Oxygen Species Receptor Activation Receptor Inhibition Reporting Research Rodent Model Role Safety Staging Stress System Therapeutic Therapeutic Effect Time Toxin Transcription Factor AP-1 Traumatic Brain Injury Work allostasis allostatic load biological adaptation to stress brain cell brain circulation brain disorder therapy cell growth cell injury cell type cerebrovascular cyclooxygenase 2 cytokine diphenyl granule cell human NOS2A protein improved insulin sensitivity interest monocyte neuroprotection novel pathogen receptor receptor expression response therapeutic effectiveness transcription factor vasoconstriction

项目摘要

Our first specific aim is to clarify the mechanisms involved in the beneficial effects of compounds which have not, until very recently, been considered of interest to the therapy of brain disorders. The second specific aim is to further establish the extent of therapeutic benefits of such compounds in diseases of the brain. We study a group of compounds collectively named sartans, or Angiotensin II AT1 receptor blockers (ARBs). Sartans are biphenyl derivatives with an excellent margin of safety, extensively used to treat cardiovascular and metabolic disorders because they antagonize Angiotensin II-induced vasoconstriction and pathological cellular growth and fibrosis, because they reduce peripheral inflammation and because they improve insulin sensitivity. Following our initial finding that sartans decrease hypertension-induced cerebrovascular inflammation, we later discovered that sartan treatment reduces brain ischemia, stress, and anxiety, and increases lifespan in rodent models. More recently, we established that the beneficial effects of sartans include a major amelioration of the negative effects of peripheral inflammation in the brain. Our conclusion was that several mechanisms may be responsible for the major neuroprotective effects of ARB treatment, and we continued studies to further clarify such mechanisms. During the current fiscal year, we advanced on the clarification of the anti-inflammatory effects of sartans in the brain. We hypothesized that at least part of the central anti-inflammatory and neuroprotective effects were the consequence of direct actions of ARBs on brain cells. The anti-inflammatory and neuroprotective effects of sartans (decline in inflammation-induced activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaBalpha) and activator protein-1 (AP-1), expression of inducible nitric oxide synthase, cyclooxygenase-2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reduction in the production of excess nitric oxide, prostaglandin E2, and reactive oxygen species leading to brain inflammation and neuronal injury) are widespread in the brain parenchyma. This suggested that sartans may influence multiple brain cell types. Using microglia, primary cortical neuron, primary cerebellar granule cell, and cerebral microvascular endothelial cell cultures, we discovered that ARBs ameliorate inflammation in all cell types studied. ARB neuroprotective effects were demonstrated against the bacterial endotoxin lipopolysaccharide (LPS), against excess glutamate and against the pro-inflammatory cytokine IL-1beta. Mechanisms involved include decreased activation of several protein kinases and reduced activation of the transcription factor NFkappaBalpha. We hypothesized that the major anti-inflammatory and neuroprotective effects of sartans may not be the exclusive result of AT1 receptor inhibition. In human circulating monocytes, cells expressing very few AT1 receptors, the anti-inflammatory effects of sartans were partially dependent on peroxisome proliferator-activated receptor gamma (PPARgamma) activation. We have found that some sartans may have dual mechanisms of action: anti-hypertensive, anti-growth and anti-inflammatory effects related to their inhibition of AT1 receptors, and metabolic and anti-inflammatory effects, partially the consequence of direct PPARgamma activation. We now confirm that participation of PPARgamma activation as a major component of ARB effects in THP-1 cells, in primary cultures of rat cortical microglia devoid of significant AT1 receptor expression, and in cerebellar granule cells from AT1A receptor knock-out mice. These results suggest that part of the beneficial effects of sartans are due to mechanisms independent of AT1 receptor stimulation. An additional novel finding is that ARB administration in a rodent model significantly protects the brain from traumatic brain injury. ARBs decrease lesion size, reduce neuronal injury and protect neurological function in this model. This is the first demonstration of the neuroprotective effect of ARBs in traumatic brain injury. Our work will not continue because the Section on Pharmacology was closed June 1st, 2013.

我们的第一个具体目标是阐明化合物的有益作用所涉及的机制，这些化合物直到最近才被认为对脑疾病的治疗感兴趣。第二个具体目的是进一步确定此类化合物在脑疾病中的治疗益处的程度。我们研究一组化合物统称为沙坦，或血管紧张素II AT 1受体阻滞剂（ARB）。沙坦是具有极好安全范围的联苯衍生物，广泛用于治疗心血管和代谢疾病，因为它们拮抗血管紧张素II诱导的血管收缩和病理性细胞生长和纤维化，因为它们减少外周炎症，并且因为它们改善胰岛素敏感性。在我们最初发现沙坦可以减少高血压引起的脑血管炎症之后，我们后来发现沙坦治疗可以减少脑缺血，压力和焦虑，并增加啮齿动物模型的寿命。最近，我们确定沙坦类药物的有益作用包括主要改善大脑中外周炎症的负面影响。我们的结论是，几种机制可能是负责ARB治疗的主要神经保护作用，我们继续研究，以进一步阐明这些机制。在本财政年度，我们进一步阐明了沙坦类药物在大脑中的抗炎作用。我们假设至少部分中枢抗炎和神经保护作用是ARB对脑细胞直接作用的结果。沙坦类药物的抗炎和神经保护作用（炎症诱导的转录因子活化B细胞的核因子κ-轻链-增强子（NF κ B α）和激活蛋白-1（AP-1）的活化的下降，诱导型一氧化氮合酶、环加氧酶-2和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的表达，过量一氧化氮、前列腺素E2的产生的减少，以及导致脑炎症和神经元损伤的活性氧）广泛存在于脑实质中。这表明沙坦可能影响多种脑细胞类型。使用小胶质细胞，原代皮层神经元，原代小脑颗粒细胞和脑微血管内皮细胞培养，我们发现ARB改善了所有研究细胞类型的炎症。ARB对细菌内毒素脂多糖（LPS）、过量谷氨酸和促炎细胞因子IL-1 β的神经保护作用已得到证实。所涉及的机制包括几种蛋白激酶的活化降低和转录因子NF κ B α的活化降低。我们假设沙坦类药物的主要抗炎和神经保护作用可能不是AT 1受体抑制的唯一结果。在人循环单核细胞中，表达很少AT 1受体的细胞，沙坦类的抗炎作用部分依赖于过氧化物酶体增殖物激活受体γ（PPARgamma）的激活。我们已经发现，一些沙坦类药物可能具有双重作用机制：与其抑制AT 1受体相关的抗高血压、抗生长和抗炎作用，以及代谢和抗炎作用，部分是直接激活PPARgamma的结果。我们现在证实，参与PPARgamma激活作为一个主要组成部分的ARB效应在THP-1细胞，在原代培养的大鼠皮质小胶质细胞缺乏显着的AT 1受体表达，并在小脑颗粒细胞从AT 1A受体敲除小鼠。这些结果表明，沙坦的部分有益作用是由于独立于AT 1受体刺激的机制。另一项新发现是，在啮齿动物模型中给予ARB可显著保护大脑免受创伤性脑损伤。在该模型中，ARB可减小病变大小，减少神经元损伤并保护神经功能。这是ARB在创伤性脑损伤中的神经保护作用的首次证明。由于药理学部分于2013年6月1日关闭，我们的工作将不会继续。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

DOI：
10.1016/j.psyneuen.2010.10.001
发表时间：
2011-01
期刊：
PSYCHONEUROENDOCRINOLOGY
影响因子：
3.7
作者：
Saavedra, Juan M.;Sanchez-Lemus, Enrique;Benicky, Julius
通讯作者：
Benicky, Julius

Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia.

DOI：
10.1016/j.regpep.2009.02.002
发表时间：
2009-04-10
期刊：
REGULATORY PEPTIDES
影响因子：
0
作者：
Imboden, Hans;Patil, Jaspal;Nussberger, Juerg;Nicoud, Francoise;Hess, Benno;Ahmed, Nermin;Schaffner, Thomas;Wellner, Maren;Mueller, Dominik;Inagami, Tadashi;Senbonmatsu, Takaaki;Pavel, Jaroslav;Saavedra, Juan M.
通讯作者：
Saavedra, Juan M.

A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH.

DOI：
10.1016/j.brainres.2008.11.006
发表时间：
2009-01-23
期刊：
Brain research
影响因子：
2.9
作者：
Macova M;Pavel J;Saavedra JM
通讯作者：
Saavedra JM

Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen

DOI：
10.1152/ajpregu.90962.2008
发表时间：
2009-05-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
影响因子：
2.8
作者：
Sanchez-Lemus, Enrique;Benicky, Julius;Saavedra, Juan M.
通讯作者：
Saavedra, Juan M.

Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition.