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

Abstract

SUMMARYPoor 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.

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…However, AT 1 receptors are localized not only in areas related to the regulation of autonomic and endocrine control, but also in many other areas of the brain responsible for emotional, sensory and motor functions. For example central Ang II through AT 1 receptors may be a specific brain modulatory factor in the control of the reaction to stress (Mayorov, 2011;Saavedra et al, 2011). Stress can affect not only the hormonal and cardiovascular system, but also the gastric mucosal integrity and can initiate gastric mucosal damage.…”

Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

“…Unfortunately it was not feasible to obtain that number of participants due to our rather strict in-and exclusion criteria ( Figure 1). All calculations were done with SPSS software package 19. Initially all variables were tested for normality visually and using the Kolmogorov-Smirnov test.…”

RETRACTION: Role of Angiotensin-(1–7) in Gastroprotection against Stress-Induced Ulcerogenesis. The Involvement of Mas Receptor, Nitric Oxide, Prostaglandins, and Sensory Neuropeptides

“…Ang II receptor subtypes AT 1 and AT 2 were detected in the human esophageal, gastric, small intestinal, and colonic mucosa (Hirasawa et al, 2002;Casselbrant et al, 2009;Hallersund et al, 2011). The antagonists of Ang II AT 1 receptors attenuated gastric injury induced by ischemia-reperfusion, cold stress, and indomethacininduced damage in rodents due to an inhibition of sympathoadrenal axis and the attenuation of vasoconstrictor and proinflammatory activity of Ang II (Pavel et al, 2008;Morsy et al, 2009;Gemici et al, 2010;Saavedra et al, 2011;Shiotani et al, 2011).…”