Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 10 Center Drive, Building 10, Room 2D-57, Bethesda, MD 20892, USA.
Psychoneuroendocrinology. 2011 Jan;36(1):1-18. doi: 10.1016/j.psyneuen.2010.10.001. Epub 2010 Oct 29.
Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective, reducing the incidence of stroke, improving cognition and decreasing the progression of Alzheimer's disease. Blockade of AT(1) receptors offers a novel and safe therapeutic approach for the treatment of illnesses of increasing prevalence and socioeconomic impact, such as mood disorders and neurodegenerative diseases of the brain.
压力适应不良、脑血管功能改变和过度脑炎症在许多精神和神经疾病的病理生理学中起着关键作用，如重度抑郁症、精神分裂症、创伤后应激障碍、帕金森病和阿尔茨海默病以及创伤性脑损伤。目前，这些高发病率和破坏性疾病的治疗方法非常有限，而且很多时候效果不佳，因此寻找新的治疗方法非常重要。最近，人们关注的焦点是一种脑调节肽——血管紧张素 II，以及其生理 AT(1)受体阻断的转化价值。除了众所周知的心血管作用外，血管紧张素 II 通过 AT(1)受体刺激，是一种多效性的脑调节因子，参与控制应激反应、调节脑血管流量和对炎症的反应。过度的脑 AT(1)受体活性与应激时交感神经和激素反应的过度增强、易患脑血管缺血和脑炎症、导致神经元损伤的过程有关。在动物模型中，用系统给予的血管紧张素 II 受体阻滞剂抑制脑 AT(1)受体活性具有神经保护作用；它可减轻过度的应激反应和焦虑，预防应激性胃溃疡，降低易患缺血和中风的风险，逆转慢性脑血管炎症，并减少由细菌内毒素引起的急性炎症反应。这些作用可保护神经元免受损伤，有助于延长寿命。血管紧张素 II 受体阻滞剂是一种安全性好的化合物，广泛用于治疗高血压，其抗炎和血管保护作用有助于减少肾和心血管衰竭。在人类中抑制脑 AT(1)受体也具有神经保护作用，可降低中风的发生率，改善认知能力，并减缓阿尔茨海默病的进展。阻断 AT(1)受体为治疗发病率和社会经济影响日益增加的疾病（如情绪障碍和大脑神经退行性疾病）提供了一种新的、安全的治疗方法。
