Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders

Abstract

Excessive allostatic load as a consequence of deregulated brain inflammation participates in the development and progression of multiple brain diseases, including but not limited to mood and neurodegenerative disorders. Inhibition of the peripheral and brain Renin-Angiotensin System by systemic administration of Angiotensin II AT(1) receptor blockers (ARBs) ameliorates inflammatory stress associated with hypertension, cold-restraint, and bacterial endotoxin administration. The mechanisms involved include: (a) decreased inflammatory factor production in peripheral organs and their release to the circulation; (b) reduced progression of peripherally induced inflammatory cascades in the cerebral vasculature and brain parenchyma; and (c) direct anti-inflammatory effects in cerebrovascular endothelial cells, microglia, and neurons. In addition, ARBs reduce bacterial endotoxin-induced anxiety and depression. Further pre-clinical experiments reveal that ARBs reduce brain inflammation, protect cognition in rodent models of Alzheimer's disease, and diminish brain inflammation associated with genetic hypertension, ischemia, and stroke. The anti-inflammatory effects of ARBs have also been reported in circulating human monocytes. Clinical studies demonstrate that ARBs improve mood, significantly reduce cognitive decline after stroke, and ameliorate the progression of Alzheimer's disease. ARBs are well-tolerated and extensively used to treat cardiovascular and metabolic disorders such as hypertension and diabetes, where inflammation is an integral pathogenic mechanism. We propose that including ARBs in a novel integrated approach for the treatment of brain disorders such as depression and Alzheimer's disease may be of immediate translational relevance.

Fig. 1

Brain inflammation participates in the development and progression of brain disorders. Excessive inflammation is one of the multiple factors increasing allostatic load. Superimposed on a background of genetic vulnerability, brain inflammation contributes to loss of homeostasis, and this may lead to neuropsychiatric diseases such as mood and neurodegenerative disorders (modified from Benicky et al. 2011)

Fig. 2

Angiotensin II and its physiological AT₁ receptors. Angiotensin II is the main mediator of the Renin–Angiotensin System, and the activity of this system is determined by the degree of AT₁ receptor stimulation. The physiological functions of AT₁ receptors include, but are not restricted to, regulation of vascular tone and blood volume, the integrity of the blood brain barrier, cerebrovascular autoregulation, the innate immune response, insulin sensitivity, sensory information, the response to stress and multiple aspects of behavior and cognition. Consequently, AT₁ receptor overactivity is involved in hypertension, blood brain barrier breakdown, vulnerability to ischemia as a consequence of loss of cerebrovascular compliance, metabolic alterations including diabetes, neuropathic pain, stress disorders, anxiety, and depression. A result of AT₁ receptor overactivity is increased peripheral and brain inflammation. AT₁ receptor overactivity may be normalized by ARB administration

Fig. 3

ARBs decrease cerebrovascular remodeling and inflammation in genetic hypertension. Genetic hypertension, such as that developing in SHR, is associated with pathological growth and fibrosis of cerebral arteries (remodeling, right figure) limiting compliance to changes in cerebrovascular flow and increasing vulnerability to brain ischemia and stroke. Cerebrovascular inflammation and macrophage infiltration of the brain parenchyma (center figure) aggravates this condition. Experimental stroke in vulnerable SHR produces major loss of brain tissue (left figure). ARB administration reverses cerebrovascular remodeling improving vascular compliance and protecting blood flow to the brain (right figure), ameliorates macrophage infiltration into the brain parenchyma (center figure), reducing inflammation, and reduces stroke damage (left figure) (modified from Nishimura et al. ; Ando et al. 2004)

Fig. 4

ARBs prevent development of stress-induced gastric ulcers. Cold-restraint stress produces massive acute gastric ulcerations (right figure), the consequence of enhanced sympathoadrenal-mediate local vasoconstriction and inflammation (left figure, representing neutrophil infiltration to the gastric mucosa). ARBs prevent gastric ulcer formation, reducing gastric mucosal vasoconstriction, and ameliorating the local inflammatory response (modified from Bregonzio et al. 2003)

Fig. 5

ARBs decrease bacterial endotoxin production and release of inflammatory factors affecting the brain. Systemic LPS administration markedly induces circulatory biomarkers of inflammation, including but not limited to IL-6, IL-1β, PGE₂, and aldosterone. Anti-inflammatory factors (corticosterone, IL-10) are also increased by LPS. Pretreatment with the ARB candesartan significantly decreases pro-inflammatory factors without affecting levels of anti-inflammatory markers. The net result is a significant decrease in the LPS-induced pro-inflammatory profile in the circulation (modified from Benicky et al. ; Sánchez-Lemus et al. 2008)

Fig. 6

ARBs decrease inflammatory stress in LPS target organs. ARBs significantly reduce LPS induction of gene expression of all inflammatory factors studied in adrenal gland, pituitary gland, and spleen, including but not restricted to IL-6 and COX-2, and PGE₂ formation in the spleen (modified from Sánchez-Lemus et al. 2008, 2009a, b)

Fig. 7

ARBs ameliorate inflammatory stress in brain structures controlling the hormonal and behavioral responses to stress. ARBs decrease LPS-induced inflammatory cascades in the brain parenchyma, including but not restricted to amelioration of LPS-induced TNF-α and IL-1β gene expression. These effects are widespread and include the subfornical organ, the hypothalamic paraventricular nucleus, controlling the HPA axis response, and the prefrontal cortex, central nucleus of the amygdala and hippocampus, involved in the behavioral responses to stress (modified from Benicky et al. 2011)

Fig. 8

ARBs reduce neuronal and microglia activation in the PVN. Candesartan reduces the number of c-fos positive neurons and the microglia activation in the PVN, as determined by expression of the specific marker OX-42 and microglial morphology (modified from Benicky et al. 2011)

Fig. 9

Direct anti-inflammatory effects of ARBs in brain cells. ARBs reduce inflammatory stress directly on brain targets for circulating inflammatory factors, the cerebrovascular endothelial cells, and in cells within the brain parenchyma, including microglia and neurons. The effects of ARBs include reduction of LPS-induced inflammatory factors, including but not restricted to TNF-α and IL-1β gene expression and release (modified from Benicky et al. 2011)

Fig. 10

Decreased LPS-induced inflammatory factors after treatment with ARBs decreases the production of inflammatory cascades in the brain and microglia activation. ARBs decrease circulating inflammatory factors (right figure), and as a consequence there is a decrease in inflammatory cascades in the brain parenchyma (center figure), followed by a decrease in activation of microglia (left figure). Decreased parenchymal inflammation protects neurons from inflammatory injury (modified from Saavedra et al. 2011)

Fig. 11

Circulating inflammatory signals stimulate target cells in the brain increasing inflammatory cascades and leading to microglia activation and neuronal damage. Circulating inflammatory factors include Angiotensin II, LPS, PGE₂, and pro-inflammatory cytokines activating interacting receptors in the cerebrovascular endothelial cells: AT₁, CD14 and TLR4, EP4 and cytokine receptors (1–4). This leads to activation of transcription factors AP-1 and NF-κB (5), with further production of inflammatory cascades within the endothelial cells and additional stimulation of inflammatory factor receptors and adhesion molecules (6–10). Enhanced release of inflammatory factors including but not limited to PGE₂, NO, TNF-α, IL-6, and IL-1β into the brain parenchyma leads to activation of microglia (11) further production of inflammatory cascades, and neuronal injury (12). Inflammatory signals generated in brain parenchyma activate microglia in the brain parenchyma and injure neurons in association with or independently of circulating inflammatory factors.

Fig. 12

Beneficial behavioral effects of ARBs. ARBs significantly reduce LPS-induced sickness behavior leading to anorexia and weight loss, and decrease anxiety in control and LPS-treated rats, as determined in the elevated plus-maze (modified from Benicky et al. 2011)

Fig. 13

Direct anti-inflammatory effects of ARBs on human circulating monocytes. ARBs ameliorate LPS-induced inflammatory responses in human circulating monocytes, including but not restricted to decreased IL-6 gene expression and reduced reactive oxygen species (ROS) formation (modified from Larrayoz et al. 2009)