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：
8342121
负责人：
JUAN M SAAVEDRA
金额：
$ 129.86万
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/8342121
关键词：
Acute monocytic leukemia Address Age Aging Aging-Related Process Agonist Alzheimer&apos s Disease Angiotensin II Animal Model Anorexia Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Anxiety B-Lymphocytes Behavior Behavioral Benzodiazepines Binding Biological Psychiatry Blood - brain barrier anatomy Body Weight decreased Brain Brain Diseases Brain Ischemia Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Line Cells Cerebrum Cessation of life Characteristics Chronic Consensus Development Diabetes Mellitus Dinoprostone Disease Encephalitis Endothelial Cells Endotoxins Enhancers Equilibrium Fibrosis Functional disorder Genetic Predisposition to Disease Glutamates Goals Growth Hormonal Human Hypertension Infiltration Inflammation Inflammatory Lead Lesion Life Light Lipopolysaccharides Longevity Major Depressive Disorder 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 Play Post-Traumatic Stress Disorders Pre-Clinical Model Prevention Production Protein Kinase Proteins Rattus Reactive Oxygen Species Receptor Activation Receptor Inhibition Reporting Research Rodent Model Role Safety Solid Staging Stress System Testing Therapeutic Therapeutic Effect Time Toxin Transcription Factor AP-1 Traumatic Brain Injury Vascular remodeling Work allostasis allostatic load base biological adaptation to stress brain cell brain circulation brain disorder therapy cell growth cell injury cell type cerebrovascular cyclooxygenase 2 cytokine diphenyl gamma-Aminobutyric Acid granule cell human NOS2A protein improved insulin sensitivity interest monocyte neuroprotection novel pathogen receptor receptor expression response therapeutic effectiveness transcription factor translational study 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. In addition we addressed the possibility that reduction of brain inflammation may have behavioral correlates, and, using validated animal models, considered the effects of sartans on anxiety and depression. 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, a human acute monocytic leukemia cell line, and in primary cultures of rat cortical microglia devoid of significant AT1 receptor expression, Our earlier findings that ARBs may limit the exaggerated hormonal and sympathetic response to stress opened a second direction of study. We have initially established that ARBs restrict the stress-induced alterations in cortical gamma-aminobutyric acid (GABAA) function, as determined by cortical benzodiazepine binding. We found, more recently, that ARBs protect GABAA function during inflammatory stress. This finding explains the anti-anxiety and anti-depressant effects of ARBs in our model of inflammatory stress (prevention of LPS-induced sickness behavior, anorexia and weight loss, and reduction of LPS-induced anxiety). We have more recently discovered, in collaborative studies, that ARBs reduce depression and anxiety associated with chronic mild variable stress in a rodent model of genetic vulnerability to depression and anxiety. We have continued to clarify the mechanisms of neuroprotection and prolongation of lifespan produced by life-long sartan administration. We found that long-term sartan administration reduces age-associated brain inflammation, vascular remodeling and anxiety, and that the neuroprotective effects of ARBs persist throughout life. Our findings may, at least in part, explain the major beneficial effects of sartan therapy in Alzheimers disease reported by other groups. 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 continues with mechanistic and translational studies to further clarify the mechanisms of ARB-induced neuroprotection and anti-depressant effects. Our goals are to test our hypothesis of major therapeutic advantages of ARB use in brain disorders,including major depression, Alzheimer's disease and traumatic brain injury, and to establish a more solid base for further development of more effective, ARB-derived neuroprotective and anti-depressant compounds of translational value.

我们的第一个具体目的是阐明化合物的有益作用所涉及的机制，直到最近才被认为是脑部疾病治疗感兴趣的。第二个具体目的是进一步确定大脑疾病中这种化合物的治疗益处的程度。我们研究一组统称为sartans或血管紧张素II AT1受体阻滞剂（ARB）的化合物。 Sartans是具有出色安全余量的双苯基衍生物，广泛用于治疗心血管和代谢性疾病，因为它们会拮抗血管紧张素II诱导的血管系和病理细胞生长和纤维化，因为它们减少了外周炎症，并且会改善胰岛素敏感性。在我们最初发现Sartans减少了高血压诱发的脑血管炎症之后，我们后来发现Sartan治疗可减少脑缺血，压力和焦虑，并在啮齿动物模型中增加寿命。最近，我们确定萨特人的有益作用包括对大脑周围炎症的负面影响的重大改善。我们的结论是，几种机制可能是ARB治疗的主要神经保护作用的原因，我们继续研究进一步阐明这种机制。在当前财政年度，我们阐明了大脑中萨坦的抗炎作用。我们假设至少部分中央抗炎和神经保护作用是ARB对脑细胞的直接作用的结果。此外，我们还解决了脑部炎症减少可能具有行为相关的可能性，并且使用经过验证的动物模型考虑了萨特人对焦虑和抑郁的影响。 sartans的抗炎和神经保护作用（炎症诱导的转录因子激活核因子核因子Kappa-Light-light-chain-chain-增强剂（NFKAPPABABALPHA）（NFKAPPABALPHA）和活化剂蛋白-1（AP-1），诱导的一氧化氮氧化氧化氧化氧化脱氧酶-2的表达（NADPH）氧化酶，过量一氧化氮的产生，前列腺素E2和导致脑炎症和神经元损伤的活性氧的产生）在脑实质中普遍存在。这表明sartans可能会影响多种脑细胞类型。使用小胶质细胞，原发性皮质神经元，原代小脑颗粒细胞和脑微血管内皮细胞培养物，我们发现ARB在所研究的所有细胞类型中都可以改善炎症。证明了ARB神经保护作用针对细菌内毒素脂多糖（LPS），对过量谷氨酸和促炎性细胞因子IL-1Beta。涉及的机制包括减少几种蛋白激酶的激活以及转录因子NFKappabalpha的激活降低。我们假设萨坦的主要抗炎和神经保护作用可能不是AT1受体抑制作用的独特结果。在人循环的单核细胞中，表达很少的AT1受体的细胞，sartans的抗炎作用部分取决于过氧化物酶体增殖物激活的受体伽马（Ppargamma）激活。我们发现，某些sartans可能具有双重的作用机制：与抑制AT1受体有关的抗高血压，抗发育和抗炎作用，以及代谢和抗炎作用，部分原因是直接ppargamma激活的结果。现在，我们确认，PPARGAMMA激活作为ARB效应的主要成分，在THP-1细胞中，人类急性单核细胞性白血病细胞系以及大鼠皮质的小胶质细胞的原代培养物，没有明显的AT1受体表达，我们较早的发现ARB可能会限制对压力的夸张的激素和交感反应，这开辟了第二个研究方向。我们最初已经确定，ARB限制了由皮质苯并二氮杂结合确定的皮质γ-氨基丁酸（GABAA）功能的应力诱导的改变。我们最近发现，ARB在炎症应激期间保护GABAA功能。这一发现解释了ARB在我们的炎症压力模型中的抗焦虑和抗抑郁作用（预防LPS诱导的疾病行为，厌食和体重减轻以及减少LPS诱发的焦虑症）。我们最近在协作研究中发现了ARB在啮齿动物遗传易受抑郁和焦虑的遗传脆弱性模型中降低了与慢性轻度可变压力相关的抑郁和焦虑。我们继续阐明神经保护的机制以及终生萨坦给药产生的寿命的延长。我们发现，长期的萨坦政府减少了与年龄相关的脑部炎症，血管重塑和焦虑，并且ARB的神经保护作用在一生中持续存在。我们的发现至少可以部分解释萨坦治疗对其他群体报道的阿尔茨海默氏病的主要有益作用。另一个新颖的发现是，啮齿动物模型中的ARB给药可显着保护大脑免受创伤性脑损伤。 ARB可降低病变的大小，减少神经元损伤并保护该模型中的神经功能。这是ARB在创伤性脑损伤中的神经保护作用的首次演示。我们的工作继续进行机械和翻译研究，以进一步阐明ARB诱导的神经保护和抗抑郁作用的机制。我们的目标是检验我们对ARB使用在脑部疾病中使用的主要治疗优势的假设，包括严重抑郁症，阿尔茨海默氏病和创伤性脑损伤，并为进一步开发更有效的，更有效的ARB神经保护性和抗抑郁药的化合物建立了更坚实的基础。