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

Abstract

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.

Published by Elsevier Ltd.

Figures

Figure 1. Mechanisms of neuronal injury leading to neuropsychiatric disease

Environmental and genetic factors interact, leading to failure of compensatory mechanisms of different degrees and with diverse localizations within the brain. The increased allostatic load to the brain translates into pathological reactivity to stress, uncontrolled inflammation and alterations in blood flow, resulting in variable degrees of neuronal dysfunction and injury. Particular combinations of alterations and their localization within the brain may affect many or selective regulatory systems. The initiation, development and combinations of particular affective, psychotic, stress-related, cognitive, and neurodegenerative diseases of the brain is dependent on the individual vulnerability, the combination of pathological factors involved, the localization of the neuronal injury, and the regulatory mechanisms affected.

Figure 2. The Renin-Angiotensin System and the regulatory functions of Angiotensin II AT1 receptors in the brain

Angiotensin II is the main active principle of the RAS, physiologically stimulating the AT1 receptor type. In the brain, Angiotensin II is a multitasking regulatory factor, involved in the regulation of stress, the autonomic and hormone systems, the circulation, and the response of the brain to endogenous and peripheral inflammation. The RAS is far more complex than originally described, and there are multiple associated and interactive synthetic and metabolic pathways, active molecules and receptors. The RAS does not function in isolation, but it is tightly related to associate regulatory systems in the brain. Decreased RAS activity may be achieved by blockade of Angiotensin II formation with Angiotensin Converting Enzyme (ACE) inhibitors or with Angiotensin II AT1 receptor blockers (ARBs).

Figure 3. The sartan molecular structures

Candesartan and other sartans (irbesartan, valsartan, olmesartan, losartan) are imidazole derivatives containing a biphenyl-tetrazole group. Telmisartan is unique, since it does not contain the tetrazole group. In addition to AT1 receptor blockade, telmisartan and to a lesser extent candesartan possess PPARγ agonist activity, a property likely to represent additional therapeutic benefit. The presence of non-Angiotensin II binding sites for some sartans has been documented but their relevance has not been clarified.

Figure 4. ARBs protect from stress and reduce anxiety?

Candesartan reduces the central sympathetic response to stress. A: Bars represent tyrosine hydroxylase mRNA expression. Open bar: isolation stress; closed bar: isolation pretreated with candesartan. * PCandesartan prevents a stress-induced disorder. B: Figures represent H&E staining of gastric mucosa. Left: rat submitted to acute cold-restraint stress; right: cold-restraint pretreated with candesartan. Acute cold-restraint stress produces multiple gastric ulcers in the rat and this is prevented by pretreatment with candesartan. Candesartan reduces anxiety. C: Bars represent time spent on the open arm of a plus maze. Open bar: vehicle-treated rat. Closed bar: rat pretreated with candesartan. Rats placed in an elevated plus maze spend increased time in the open arm, a sign of decreased anxiety, when pre treated with candesartan. Modified from Bregonzio et al., 2008 (A), Bregonzio et al., 2003 (B) and Saavedra et al., 2006 (C).

Figure 5. ARBs reverse cerebrovascular remodeling and inflammation and reduce ischemia and stroke in SHR

Candesartan reverses cerebrovascular remodeling. A: Figures are H&E images of middle cerebral artery in untreated SHR (left) and after candesartan treatment (right). Chronic hypertension in SHR leads to cerebrovascular remodeling with increased medial thickness and decreases compliance. Candesartan reverses remodeling and arterial stiffness, restoring compliance to changes in blood pressure and protecting from ischemia.This reverses the cerebrovascular stiffness and decreased compliance to changes in blood pressure. Candesartan reverses chronic cerebrovascular inflammation in hypertension. B: Immunostaining with macrophage-microglia specific ED-1 antibody. Figure on the left reveals macrophage infiltration in a microvessel located in the cerebral cortex of an SHR, reversed by treatment with candesartan (figure on the right). Candesartan reduces brain ischemia and stroke volume. C: Candesartan decreases experimental stroke as a consequence of permanent ligation of a branch of the middle cerebral artery in SHR. Figure on the left: untreated SHR, section visualized with the 2, 3, 5-triphenyltetrazolium chloride method to determine volume of tissue damage. Figure on the right: decreased stroke volume in SHR pretreated with candesartan. Modified from Ando et al., 2004 (A and B) and Nishimura et al., 2000 (C).

Figure 6. ARBs decrease peripheral and brain inflammation produced by systemic administration of bacterial endotoxin

Candesartan reduces peripheral inflammation produced by LPS. A: Bars represent the concentration of plasma aldosterone (left figure) and plasma IL-6 (right figure). Open bars: rats injected with LPS; closed bars: pretreatment with candesartan and injected with LPS. * P Candesartan decreases microglia activation. C: Figures represent microglia in cerebral cortex of rats injected with LPS (left figure) and pretreated with candesartan and injected with LPS (right figure). Microglia were stained with OX-42 antibody. (Modified from Sánchez-Lemus et al., 2009b) (A) and Benicky et al., 2009 (B and C).

Figure 7. Proposed role of Angiotensin II AT1 receptors in bacterial endotoxin-induced brain inflammation

Systemic administration of LPS increases circulating inflammatory factors targeting cerebrovascular endothelial cells, followed by activation of pro-inflammatory transcription factors such as NF-κB and AP-1. This leads to activation of inflammatory cascades with production and release of inflammatory factors into the brain parenchyma. Circulating macrophages infiltrate the brain parenchyma as a consequence of blood-brain barrier breakdown and upregulation of adhesion molecules, provoking a further enhancement of inflammatory cascades. Excess pro-inflammatory factors activate resident microglia and astrocytes with additional increase of inflammatory signals. Unregulated inflammation leads to neuronal injury and brain disease. The neuroprotective effect of ARBs is the consequence of the reduction of circulating inflammatory factors, blockade of pro-inflammatory AT1 receptors in cerebrovascular endothelial cells, protection of the blood-brain barrier and reduction of macrophage infiltration. Additional neuroprotective effects may result from AT1 receptor blockade in parenchymal microglia, astrocytes and neurons. AP-1: activator protein 1. COX-2: cyclooxygenase-2. EP2/4: prostaglandin E receptors 2/4. iNOS: inducible nitric oxide synthase.. MR: mineralocorticoid receptor. NF-κB: nuclear factor κB. NO: nitric oxide. Nox: NADPH oxidase. PGE2: prostaglandin E2. ROS: reactive oxygen species. TLR4: toll-like receptor 4.