American Journal of Hypertension Advance Access published October 31, 2014

State of the Art

Neuroprotective Effects of Angiotensin Receptor Blockers Sonia Villapol1 and Juan M. Saavedra2 selective for only some compounds of the class. These include peroxisome proliferator-activated receptor gamma activation and other still poorly defined mechanisms. However, the complete pharmacological spectrum and therapeutic efficacy of individual ARBs have never been systematically compared, and the neuroprotective efficacy of these compounds has not been rigorously determined in controlled clinical studies. The accumulation of pre-clinical evidence should promote further epidemiological and controlled clinical studies. Repurposing ARBs for the treatment of brain disorders, currently without effective therapy, may be of immediate and major translational value.

Angiotensin II (Ang II) receptor blockers (ARBs, collectively called sartans) were developed to normalize high blood pressure associated with excessive peripheral Ang II type 1 receptor (AT1R) activity. It was later recognized that ARBs ameliorate peripheral inflammation and exhibit major beneficial effects on metabolism. ARBs are now widely used for the therapy of cardiovascular disorders, renal disease, and alterations in metabolism including diabetes.1,2 In addition, ARBs are powerful neuroprotective agents.3 Major and interacting pathogenic factors, associated with enhanced AT1R activation, link cardiovascular, metabolic, and brain disorders: alterations in the vasculature and excessive, toxic inflammation, leading to hypoxia, reduced nutrient supply, and vulnerability to cell injury.4,5 This explains how hypertension, renal disease, and metabolic disorders affect the brain, why these conditions are recognized risk factors in neurodegenerative processes such as Alzheimer’s disease,4–8 and how compounds of therapeutic efficacy in “peripheral” disorders also ameliorate brain disease. ARBs protect the peripheral and brain vasculature, reduce hypoxia and decrease peripheral and brain inflammatory injury.3,9 For these reasons, decreasing excessive AT1R activity has the potential to ameliorate a large number of brain disorders.

The present review will consider the heterogeneity of the ARB class, their differential pharmacological profiles, the main established mechanisms of action, the possible participation of additional pathways, the evidence of neuroprotection, limitations and pitfalls in pre-clinical and clinical research, and future directions to facilitate testing the most promising ARB in controlled clinical settings.

Correspondence: Juan M. Saavedra ([email protected]). Initially submitted July 7, 2014; date of first revision July 23, 2014; accepted for publication September 17, 2014.

Keywords: Alzheimer’s disease; angiotensin II; angiotensin receptor blockers; blood pressure; brain inflammation; hypertension; neuronal injury; neuroprotection; neurodegenerative disorders; Parkinson’s disease; renin–angiotensin system; sartans; traumatic brain injury. doi:10.1093/ajh/hpu197

THE RENIN–ANGIOTENSIN SYSTEM AND THE AT1Rs

The renin–angiotensin system is a major regulatory system with an active principle, Ang II, effective through AT1R stimulation (Figure  1), and expressed in most organs including the brain.10 AT1Rs are highly expressed in cerebrovascular endothelial cells,10,11 explaining how Ang II stimulation and AT1R blockade, by controlling cerebrovascular flow and the function of the blood-brain barrier, contributes to regulate the overall function of the brain. AT1Rs are also expressed in widespread but selective neuronal circuits10 and in astrocytes.12 This explains how AT1R activity regulates multiple brain functions, including but not restricted to central sympathetic and hormonal systems, the reaction to stress, cognition, and the control of the innate immune response. For a complete

1Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA; 2Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA.

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Angiotensin II receptor blockers (ARBs, collectively called sartans) are widely used compounds therapeutically effective in cardiovascular disorders, renal disease, the metabolic syndrome, and diabetes. It has been more recently recognized that ARBs are neuroprotective and have potential therapeutic use in many brain disorders. ARBs ameliorate inflammatory and apoptotic responses to glutamate, interleukin 1β and bacterial endotoxin in cultured neurons, astrocytes, microglial, and endothelial cerebrovascular cells. When administered systemically, ARBs enter the brain, protecting cerebral blood flow, maintaining blood brain barrier function and decreasing cerebral hemorrhage, excessive brain inflammation and neuronal injury in animal models of stroke, traumatic brain injury, Alzheimer’s and Parkinson’s disease and other brain conditions. Epidemiological analyses reported that ARBs reduced the progression of Alzheimer’s disease, and clinical studies suggested amelioration of cognitive loss following stroke and aging. ARBs are pharmacologically heterogeneous; their effects are not only the result of Ang II type 1(AT1) receptor blockade but also of additional mechanisms

Villapol and Saavedra

structure, individual ARBs may bind to different receptor domains, their mechanisms of receptor antagonism may vary, and because of their differential lipophilicity they may present major differences in tissue penetration, dissociation kinetics, biological half-life and bioavailability. These differential characteristics have been recently and comprehensively reviewed.18 However, logistical difficulties have prevented comparing individual ARBs under similar experimental or clinical conditions, and determination of the most effective compound of the class for the treatment of a particular cardiovascular or metabolic disorder remains elusive. Lack of systematic experimental and clinical comparative studies makes selection of the most efficacious ARB for the treatment of brain disorders even more problematic.3

ARBs, administered systemically—intraperitoneally, subcutaneously, or orally—are neuroprotective in a large number of rodent models of brain disorders. While these findings indicate direct actions in the brain, indirect mechanisms may contribute to different degrees to their preclinical efficacy (Figure 2). Neuroprotection may be the result of direct blockade of brain AT1Rs, a consequence of AT1R blockade outside of the brain, or respond to processes additional to the class effect of AT1R antagonism. Figure 1.  The renin–angiotensin system (RAS). The active principle of the RAS, Angiotensin (Ang) II, is formed by renin activation, transforming the substrate Angiotensinogen into Ang I, in turn cleaved by the Angiotensin Converting Enzyme (ACE) into Ang II. Ang II type 1 receptors (AT1R) are responsible for the physiological effects of RAS. Abnormal stimulation of AT1Rs by excessive Ang II formation or increased AT1R activity may lead to disease. The overactive RAS may be controlled by decreasing Ang II formation with renin or ACE inhibitors, or by blocking the AT1Rs with Angiotensin Receptor Blockers, also called sartans. Additional pathways have been proposed to interact with the classical RAS system. They include: metabolism of Angiotensinogen by kallikrein to directly yield Ang (1–12), followed by chymase to produce Ang II; formation of Ang (1–9) from Angiotensinogen or from Ang I  by ACE2, followed by Ang (1–7) formation from Ang (1–9) by ACE, and from Ang II by ACE2, and production of Ang (1–7) directly from Ang I by neutral endopeptidase (NEP). In turn, Ang (1–7) activates the Mas receptors. Ang II may also be cleaved to Ang III by Aminopeptidase A (APA), followed by cleavage by Aminopeptidase N (APN) to generate Ang IV. A role for Ang III and Ang IV has been proposed through stimulation of AT1R and insulin-regulated membrane aminopeptidase (IRAP), respectively. The consequences of Ang (1–7) and Ang IV activities are under study. Ang II stimulates a second receptor type, the Ang II type 2 receptor (AT2R), proposed to exert neuroprotective effects and to counterbalance neurotoxic effects of AT1R overstimulation.

examination of the complexity of the renin–angiotensin system and the ever-expanding evidence of multiple regulatory functions, readers may wish to consult the following reviews.3,10,13–17 THE ARB GROUP

ARBs are imidazole derivatives with a common class effect, the blockade of AT1R. There are 8 clinically available ARBs (Table 1). On the basis of differences in chemical 2  American Journal of Hypertension

Direct effects in the brain

• Evidence of direct penetration into the brain. At present, the strongest evidence for direct penetration into the brain after systemic administration, reaching therapeutically relevant concentrations, has been reported for telmisartan in rats, primates, and humans.19,20 • Indirect evidence of central effects. Indirect indication of effects in parenchymal neurons and glia are observed after systemic administration and include autoradiographic evidence of central AT1R blockade, blockade of effects of Ang II administered directly into the brain, and reduction of brain parenchymal inflammation.21–24 Penetration through the blood-brain barrier could be regulated by specific transporters, be dependent on the compound’s lipophilicity, highest for telmisartan when compared with other members of the group,18 or be in part dependent on transport through the olfactory epithelium with anterograde progression into the temporal lobe.25,26 Transport of ARBs into the brain may increase after chronic administration, or in pathological circumstances leading to breakdown of the blood-brain barrier, such as hypertension and traumatic brain injury.27 Direct neuroprotection has also been demonstrated, in particular for candesartan and telmisartan, in primary neuronal, astrocyte, microglia and cerebrovascular endothelial cell cultures, and for injury factors with major roles in brain disease, such as glutamate excitotoxicity, excessive proinflammatory interleukin-1beta (IL-1β), bacterial endotoxin (lipopolisaccharide (LPS)), and hypoxia21,22,28–32 (Figure 3).

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MECHANISMS OF ARB NEUROPROTECTION

ARBs are Neuroprotective Table 1.  Angiotensin II receptor blockers Drug

Trade name

Biological half-life (hours)

Losartan

COZAAR

6–9

33

50–100

Candesartan

ATACAND

9

15

4–32

Telmisartan

MICARDIS

24

42–58

40–80

DIOVAN

6

25

80–320

Valsartan

Bioavailability (%)

Daily dosage (mg)

Irbesartan

AVAPRO

11–15

70

150–300

Olmesartan

BENICAR

14–16

29

10–40

Azilsartan

EDARBI

11

60

40–80

Eprosartan

TEVETEN

5

13

400–800

Effects of circulating ARBs in the brain

These actions do not require penetration into the brain parenchyma. The principal mechanisms are (Figure 2): • Control of the cerebral circulation. ARBs regulate cerebral blood flow by blocking AT1Rs in cerebrovascular endothelial and vascular smooth muscle cells in large cerebral arteries and the microvasculature.10,11 The microvascular density in the human brain is 2500–3000/mm3, and the mean separation between adjacent capillaries in the human brain is about 40 µm,33 ensuring that modulation

of AT1R activity may influence overall brain function. ARBs oppose Ang II-driven pathological increases in vasoconstriction and vascular hypertrophy and remodeling, thus reducing brain ischemia, vulnerability to stroke or cell death following traumatic brain injury.34–37 • Control of neuronal AT1Rs in circumventricular organs located outside the blood-brain barrier. Circumventricular organs express high AT1R concentrations, located in fenestrated capillaries and in neurons with access to circulating drugs, and participating in circuits regulating the central sympathetic and hormonal systems.38 American Journal of Hypertension  3

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Figure 2.  How might systemically administered, circulating ARBs influence the brain. Following oral administration, circulating ARBs may have central effects on the brain regulating cerebral blood flow, directly on circumventricular organ AT1R outside the blood brain barrier, or preserving the function of the blood-brain barrier. In addition, ARBs are transported into the brain, where they directly stimulate neuronal and glial AT1R. In combination, circulating and parenchymal ARBs contribute to regulate multiple brain functions. These include regulation of stress, inflammation, behavior and sensory and motor control. After oral intake, effects of AT1R blockade in peripheral organs also affect the brain. Mechanisms include regulation of pituitary hormone production and release, the response to stress, peripheral sympathetic nerve activity, pain perception, and the function of many peripheral organs by AT1R blockade in blood vessels, macrophages, and parenchymal cells. Abbreviations: ARB, Angiotensin Receptor Blocker; AT1R, Ang II type 1 receptor.

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• Protection of the blood-brain barrier. Maintaining the integrity of the blood-brain barrier is a major neuroprotective mechanism. Damage to the blood-brain barrier contributes 4  American Journal of Hypertension

to infiltration of macrophages and passage of circulating injury factors to the brain parenchyma, documented in large numbers of brain conditions including hypertension,

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Figure 3.  Signaling pathways regulated by ARBs. Overstimulation of AT1Rs increases inflammatory and apoptotic signaling. Mechanisms include interaction with membrane receptors and signaling pathways for injury factors (interleukin-1beta (IL-1β), lipopolisaccharide, Angiotensin II (Ang II), glutamate) leading to enhance cell injury. Augmented nicotinamide adenine dinucleotide phosphate activation and increased oxidative stress with enhanced formation of reactive oxygen species (ROS) leads to mitochondrial dysfunction with excessive formation of mitochondrial ROS, enhancing both inflammation and apoptosis. Additional inflammatory mechanisms include activation of cyclooxygenase-2 with production of inflammatory prostaglandins, increased toxic levels of nitric oxide and stimulation of the diacylglycerol/protein kinase c/ extracellular signal-regulated kinases 1 and 2 pathway. The result is increased intranuclear trafficking of transcription factors such as nuclear factor-kappaB with enhanced production of pro-inflammatory, neurotoxic cytokines, such as IL-1β, tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1. Pro-apoptotic mechanisms include reduction of survival pathways such as the phosphoinositide-3-kinase/ protein kinase B/Akt/glycogen synthase kinase 3 beta pathway, activation of caspase-3, and stimulation of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK). Further, AT1R overstimulation inhibits the neuroprotective peroxisome proliferator-activated receptor gamma (PPARγ). By blocking AT1R overstimulation, ARBs reduce expression of membrane receptors activated by injury factors (IL-1R1, CD14, TLR4, NMDA) their corresponding apoptotic and inflammatory signaling and PPARγ inhibition. In addition, some ARBs directly activate PPARγ even in the absence of AT1R, The reduction of multiple neurotoxic factors and the stimulation of neuroprotective signaling pathways which follows ARB administration leads to reduction of inflammation and neuronal injury, protection of blood flow, and improved energy balance. Combined, these effects protect cognition, reduce stress, anxiety and depression, and may increase lifespan. Abbreviations: ARB, angiotensin receptor blocker; AT1R, ang II type 1 receptor; IL-1R1, interleukin-1 receptor type 1; NMDA, N-methyl-d-aspartate.

ARBs are Neuroprotective

Alzheimer’s disease, diabetes, and traumatic brain injury. ARBs protect the blood-brain barrier in these conditions, a benefit contributing to amelioration of cognitive loss.39,40 Peripheral effects

In addition to direct effects on brain cells, ARB neuroprotection may be the result of indirect mechanisms on peripheral organs (Figure 2, Table 2): • Regulation of pituitary hormone production and release. ARBs regulate hormone production and release by

blocking AT1Rs in parenchymal anterior pituitary cells controlling reproductive hormones and the reaction to stress.10 In the adrenal zona glomerulosa, AT1Rs regulate the production and release of aldosterone, a major proinflammatory factor in the brain and periphery.17 • Regulation of the response to stress. In addition to their influence on the central response to stress, ARBs regulate the associated sympathetic and hormonal peripheral responses (see above) and adrenaline release from the adrenal medulla.3 • Influence on the peripheral sympathetic nerve activity. AT1Rs are located in all sympathetic nerve terminals regulating norepinephrine release, peripheral sympathetic

Table 2.  Neuroprotective effects of angiotensin II receptor blockers Mechanism of injury

ARB-specific effects

References

Glutamate excitotoxicity

reduce apoptosis, protects survival pathway PI3K/ Akt/GSK-3β, reduce ERK1/2 activation, enhance PPARγ activation and reduce inflammation

Shigematsu et al.38

Pro-inflammatory IL-1β

reduce cyclooxygenase-2 expression and PGE2 production and release, reduce IL-1β receptor (IL1R1) transcription, NADPH oxidase-4 transcription and activity, decrease oxidative stress, decrease c-Jun N-terminal kinase

Nishimura et al.36

Bacterial endotoxin (LPS)

reduce TNF-α and monocyte chemotactic protein-1, decrease nuclear factor-κB (NF-κB) activation, prevent the production of IL-1β and TNF-α in neurotoxic amounts, ERK1/2 or p38 mitogenactivated protein kinase phosphorylation and NF-κB activation

Obermeier et al.27

Hypoxia

reduce NADPH oxidase activity via activation of PKC, enhance formation of excessive cytoplasmic and mitochondrial ROS

Khoury et al.71

Bacterial endotoxin (LPS)

repress NF-κB activation, reduce proinflammatory cytokine and prostaglandin transcription, cytokine receptors, adhesion molecules, proinflammatory inducible enzymes, and microglia activation

Obermeier et al.27, Danielyan et al.28, Pang et al.29, Pang et al.30

Traumatic brain injury

decrease lesion volume and inflammation; protect motor performance and cognition

Nishimura et al.23

Genetic hypertension

reduce blood pressure, protect the blood-brain barrier

Benicky et al.21, Pang et al.29, Hawkes et al.26

Stroke

improve cerebrovascular autoregulation, ameliorate ischemia

Benicky et al.22, Min et al.39, Sanchez-Lemus et al.47

Alzheimer’s disease and cognition

reduce early etiological factors, such as chronic hypoxia and neurotoxic inflammation

Benicky et al.22, Obermeier et al.27, Min et al.39, Tsukuda et al.50, Iadecola51

Parkinson’s disease

protect dopaminergic cells from injury

Wincewicz et al.56

Anxiety and depression

reduce peripheral and central responses to multiple stressors

Saavedra3

Stroke

ameliorate stroke, protects cognition and motor performance, before and after stroke

Saavedra3, Baiardi et al.60, Min et al.39

Alzheimer’s disease and cognition

ameliorate risk factors: hypertension, stroke, and diabetes; delay disease progression, preserves executive function, and cognition

Horiuchi et al.64, Mogi et al.65

Mood disorders

reduce stress, anxiety, and depression

Hajjar et al.69

Preclinical studies

Clinical studies

Abbreviations: ARB, angiotensin receptor blocker; AT1R, ang II type 1 receptor; ERK1/2, extracellular signal-regulated kinases 1 and 2; GSK-3β, glycogen synthase kinase 3 beta; IL-1β, interleukin-1beta; IL-1R1, interleukin-1 receptor type 1; LPS, lipopolisaccharide; NADPH, nicotinamide adenine dinucleotide phosphate; PGE2, prostaglandin E2; PI3K, phosphoinositide-3-kinase; PKC, protein kinase c; ROS, reactive oxygen species.

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In vitro

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aldosterone release, reaching the circulation and influencing the brain.21 ARBs ameliorate macrophage activation in the spleen following LPS administration, and reduce the inflammatory response of circulating human monocytes.29,47 These multiple mechanisms may be associated with the reported reduction of brain inflammation in a number of animal models of brain disorders including genetic hypertension, stroke, and experimental autoimmune encephalomyelitis.3 EVIDENCE FROM IN VIVO ANIMAL MODELS OF DISEASE (Figure 4)

1. Traumatic brain injury. ARBs are neuroprotective in a rodent model of single controlled cortical impact injury, decreasing lesion volume and inflammation and protecting motor performance and cognition.37 2. Stroke. During hypertension, remodeling of the brain vasculature alters cerebrovascular autoregulation, leading to chronic hypoxia and vulnerability to stroke. Sustained ARB treatment normalizes blood pressure and reverses cerebrovascular remodeling, improving cerebrovascular autoregulation in animal models of hypertension.17,34,36 It appears that amelioration of ischemic conditions is a general beneficial effect, since ARBs also reduce retinal ischemia.48

Figure 4.  Neurotoxic mechanisms reduced by ARBs and associated with brain disorders. Pathological factors in the brain induce excessive oxidative stress, cerebral blood flow alterations such as ischemia and dysregulation of cerebrovascular autoregulation, mitochondrial dysfunction, neurotoxic inflammatory processes and increased production, and accumulation of toxic Amyloid-β proteins. These phenomena cause prominent neuronal and axonal injury associated with traumatic brain injury, spinal cord injury, stroke, dementia and Alzheimer’s and Parkinson’s diseases, and mood disorders. By decreasing the pathogenic mechanisms, enhancing neuroprotection, ARBs may ameliorate the development and progression of multiple brain disorders, improving their outcome and reducing disability. Abbreviation: ARB, angiotensin receptor blocker.

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activity, blood flow, and therefore the function of multiple organs indirectly signaling the brain.41,42 • Regulation of vagal activity and transport. The dorsal motor nucleus of the vagus and the nucleus of the solitary tract express large numbers of AT1Rs43 in part originated in the vagal ganglia and transported to the brain.44 ARBs may prevent the transfer of inflammatory signals reaching the brain through the vagus.45 Neurotropic pathogens in the intestine may enter axons of the Meissner’s plexus and trans-synaptically reach the preganglionic parasympathetic motor neurons of the vagus nerve.26 Whether this is a significant mechanism related to the etiology of brain disorders, as proposed,26 and whether ARBs influence such mechanism has not been determined. • Regulation of pain perception. ARBs exert anti-inflammatory effects that may decrease chronic neuropathic pain induced by nerve constriction.46 This effect may be related to their significant anti-inflammatory effects. • Influence on peripheral organ function by AT1R blockade in blood vessels, macrophages and parenchymal cells. ARBs contribute to regulate the innate immune response, ameliorating peripheral inflammation and the associated brain inflammatory response.21 These effects may be the combination of direct anti-inflammatory effects on microglia, protection of the blood-brain barrier, therefore reducing macrophage infiltration into the brain, and reduction of pro-inflammatory cytokines and

ARBs are Neuroprotective

EVIDENCE FROM CLINICAL STUDIES

1. Stroke. The strongest evidence for a therapeutic benefit of ARB administration is associated with controlled, randomized clinical studies in stroke, and was recently reviewed.3 Benefits of ARB administration may be obtained by their use as preventive treatment62 but the value of post-stroke ARB administration has also been consistently reported.17 2. Dementia and Alzheimer’s disease. ARBs reduce all major risk factors for Alzheimer’s disease, controlling hypertension, limiting stroke damage, and ameliorating diabetes.63–65 Epidemiological studies reported that ARBs have superior neuroprotective benefits, delaying disease progression,66,67 and preserving executive function and cognition better than other anti-hypertensive drugs.68,69 However, the evidence for effectiveness of ARB treatment for Alzheimer’s disease is still inconclusive,70 in particular because clinical trials have been conducted in patients with advanced disease, in heterogeneous populations and for short periods. 3. Mood Disorders. ARBs improve the quality of life and reduce stress, anxiety, and depression not only in hypertensive but also in normotensive individuals and those

affected with diabetes, demonstrating a good correlation between the pre-clinical findings and observational studies in humans.3 A recent epidemiological study reported amelioration of post-traumatic stress disorder in patients under ARB treatment.71 MOLECULAR MECHANISMS OF ARB NEUROPROTECTION Direct angiotensin II toxicity

The molecular mechanisms of Ang II-induced toxicity have been extensively studied in peripheral cells.72,73 Established mechanisms of Ang II-induced toxicity include increased nicotinamide adenine dinucleotide phosphate oxidase activity, leading to intracellular generation of reactive oxygen species. Subsequently, increased reactive oxygen species production activates redox-sensitive signaling molecules, such as mitogen-activated protein kinases, e.g., p38 mitogen-activated protein kinases, NH2-terminal kinases (JNK), and extracellular signal-regulated kinases 1 and 2 (Figure 3). In addition, Ang II directly enhances cellular and mitochondrial oxidative stress.16,74 Ang II-induced activation of transcription factors such as nuclear factor-κB (NF-κB) promotes increased production of inflammatory cytokines such as of IL-1β, tumor necrosis factor alpha and interleukin-6, and chemokines such as monocyte chemoattractant protein-1.16,73 Furthermore, Ang II-induced NF-κB activation and downregulates the anti-inflammatory peroxisome proliferator-activated receptors (PPARs) (Figure  3).3 The result is a significant inflammatory response and increased apoptosis, well characterized in peripheral vascular cells16,73 (Figure 3). Neuroprotective signaling pathways

Proposed molecular mechanisms of Ang II-induced neurotoxicity have been revealed only after ARB administration using primary cultures of brain cells and animal models of disease. Neuroprotection, including reduction of apoptosis and neurotoxic inflammation, has been validated not as a consequence of decreased Ang II toxicity, but as a result of protection against a number of injury factors, including complex interactions with their membrane receptors and signal transduction mechanisms.3 • Neuroprotection from bacterial endotoxin. ARB neuroprotection against bacterial endotoxin (LPS) has been extensively studied. LPS is a major toxin characteristic of gram-negative bacteria. LPS-induced inflammation and apoptosis is the result of activation of membrane tolllike receptors (TLRs) such as TLR4 and its co-receptor CD14.21 There is strong evidence that ARBs significantly reduce LPS-induced stimulation of CD14 and TLR4.21 Two principal mechanisms of ARB neuroprotection from LPS injury have been described: • Reciprocal regulation of TLR4-CD14 and AT1R expression. In primary neuronal cultures, LPS up regulates AT1R expression, while ARBs down-regulate CD14 transcription, decreasing LPS effects at the receptor level21 (Figure 3). American Journal of Hypertension  7

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3. Dementia and Alzheimer’s disease. Beneficial effects of ARB treatment beyond their effects on blood pressure, including protection of cognition, have been reported in rodent models of Alzheimer’s disease.49,50 Neuroprotection may be the consequence of reduction of early etiological factors, such as chronic hypoxia and neurotoxic inflammation.17,21,36,51,52 Protection of cognition appears to be a general beneficial ARB effect, because it has been demonstrated in streptozotocin-induced diabetes, scopolamine administration, whole-brain irradiation, and stress53–56 4. Parkinson’s disease. In rodent models of Parkinson’s disease, excessive brain AT1R stimulation enhances inflammation and injures dopaminergic cells. Consequently, it was hypothesized, and confirmed, that ARB neuroprotection is associated with protection of dopaminergic cells from injury.57 5. Depression and anxiety. Numerous studies reviewed in detail elsewhere demonstrated that when administered to rodents, ARBs reduce the peripheral and the central response to multiple stressors, including isolation, restraint and peripheral and brain inflammation; prevent stress-induced disorders such as cold-restraint induced gastric ulcerations, and ameliorate anxiety,3 and enhance the extinction of fear memory.58 6. Increase in lifespan. Decreasing AT1R activity promotes longevity in genetically hypertensive rats.59 Mechanisms involved may include reduction in stress-related catecholamine and vasopressin release60 and protection of heart and kidney injury.59 The increase in lifespan associated with reduced AT1R activation is not restricted to hypertension, because knockout of the angiotensin II type 1a receptor subtype (AT1aR) gene markedly prolongs lifespan in normotensive mice, a mechanism probably associated with reduction of oxidative damage, protection of mitochondrial function and overexpression of prosurvival genes such as sirtuin 3.61

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Evidence for ARB effects additional to AT1R blockade: The role of PPARγ.  Some ARBs exert beneficial effects not directly associated with AT1R blockade,76 in cell cultures 8  American Journal of Hypertension

lacking Ang II,21,29,30,32 in cells not expressing AT1Rs, such human circulating monocytes and rodent microglia21,29,30,32 and in AT1R knockout mouse models and their cultured neurons.32,77–79 ARB neuroprotection occurs at concentrations below those needed for substantial AT1R blockade or to change blood pressure, and is superior to that of other anti-hypertensive drugs.23,35 Telmisartan, and to a lesser extent candesartan and losartan, activate the PPAR gamma (PPARγ),29,37,80–82 a member of a family of ligand-activated transcription factors with three known members, PPAR alpha, PPAR beta/delta and PPARγ.77 PPARγ activation benefits carbohydrate and lipid metabolism77 and directly protects the vasculature,80 and ARB beneficial effects include protection of the vasculature and improvement of insulin sensitivity and glucose metabolism.83 The net result of AT1R blockade and PPARγ activation is to improve energy balance and blood flow to the brain (Figure 3). PPARγ activation by ARBs has been demonstrated in cell cultures and rodent models of brain disorders such as Alzheimer’s disease,29,37,50,81,84–87 decreasing inflammation and protecting cognition.29,32,37 AT1R blockade and PPARγ activation may be independent neuroprotective properties. However, AT1R stimulation decreases PPARγ induction while PPARγ activation reduces AT1R stimulation,17 indicating that the effects of ARBs on PPARγ may not be necessarily independent of AT1R blockade (Figure 3). In addition, there is a reciprocal interaction between LPS toxicity and PPARγ activation. While PPARγ activation reduces LPS toxicity, LPS inhibits PPARγ induction.88,89 The conclusion is that AT1R, PPARγ, and CD14/TLR4 are closely related. Neurotoxic inflammation occurs when AT1R and CD14/TLR4 predominate over PPARγ stimulation. This explains the strong neuroprotection offered by some ARBs. Additional neuroprotective effects in addition to AT1R blocking/PPARγ activation. Telmisartan neuroprotection has been demonstrated in systems: (i) not expressing AT1Rs, (ii) not mimicked by PPARγ agonists, and (iii) not influenced by PPARγ antagonism.90–92 These effects may be partially explained by the radical scavenging properties of telmisartan.92 Additional mechanisms may recruit the participation of other members of the PPAR triad,77 PPAR alpha and PPAR beta/delta,83,93,94 or regulation of selective microRNAs, such as microRNA-155 (miR-155), a microRNA that physiologically reduces AT1R expression.95 Effects of selected ARBs on thromboxane A2 receptor blockade, decreased platelet aggregation, and reduction of serum uric levels have been mentioned as partial determinants of beneficial effects.96 However, at present no clinical evidence is available in support of their therapeutic advantages for the treatment of cardiovascular disease,96 and nothing is known regarding their influence for the treatment of brain disorders. Is there a role for AT2Rs?  In addition to AT1Rs, Ang II binds to AT2R (Figure 1). AT2R stimulation has been proposed to counterbalance AT1R activity.97 ARBs, by blocking AT1Rs and increasing Ang II production, may increase AT2Rs activation and enhance mechanisms of neuroprotection. However, the importance of AT2Rs in brain disorders

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Inhibition of common signal transduction pathways. ARBs reduce pro-inflammatory signal transduction mechanisms common to CD14/TLR4 and AT1R stimulation, such as the activation of NF-κB. In turn, NF-κB induction leads to enhance intracellular inflammatory cascades with neurotoxic production of IL-1β, tumor necrosis factor alpha and interleukin-6, effects associated with increased oxidative stress.3,21 Similar anti-inflammatory effects were noted in cultures from non-neuronal LPS target cells, such as cerebrovascular endothelial cells and primary microglia,21 and in circulating human monocytes infiltrating the brain during peripheral inflammatory conditions and brain injury.29 In cultured monocytes, ARB neuroprotective effects include monocyte chemoattractant protein-1 (Figure 3) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression, and decreased monocyte chemoattractant protein-1 directed migration.29 • In vitro evidence of ARB neuroprotection of LPS-induced injury is supported by in vivo studies. ARB administration prevented brain inflammation as a result of systemic LPS administration.21 In vivo mechanisms include decreased production and release into circulation of centrally acting proinflammatory cytokines, repression of brain NF-κB activation, reduction of brain proinflammatory cytokine and prostaglandin transcription, cytokine receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation.21 • Neuroprotection against IL-1β injury. ARBs directly protect neuronal cultures from the inflammatory and pro-apoptotic effects of excessive IL-1β stimulation. ARBs reduce, in primary cortical neurons, the enhanced cyclooxygenase-2 expression and prostaglandin E2 production and release induced by neurotoxic concentrations of IL-1β (Figure 3).30 In primary neuronal cultures, neuroprotective mechanisms include extracellular signal-regulated kinases 1 and 2 or p38 mitogen-activated protein kinases phosphorylation and NF-κB activation (Figure 3).21 In cultured neuroblasts, neuroprotection against IL-1β-induced neurotoxicity includes reduction of the interleukin-1 receptor type 1 and nicotinamide adenine dinucleotide phosphate oxidase-4 transcription and activity, decreased oxidative stress and hydrogen peroxide-induced cyclooxygenase-2 transcription, effects associated with a decrease in JNK30 (Figure 3). • Neuroprotection against glutamate toxicity. ARB administration reduces neuronal injury produced by N-methylD-aspartate receptor stimulation by neurotoxic glutamate concentrations (Figure 3).32 Neuroprotection mechanisms include decreased N-methyl-D-aspartate receptor expression,75 reduction of glutamate-induced pro-apoptotic caspase-3 activation, protection of the survival pathway phosphoinositide-3-kinase/protein kinase B/Akt/ glycogen synthase kinase 3 beta, and reduction of neurotoxic inflammation.32Conversely, excessive N-methylD-aspartate receptor activation up regulates AT1R transcription and expression, thus enhancing pro-apoptotic and pro-inflammatory AT1R activity32 (Figure 3, Table 2).

ARBs are Neuroprotective

is still not clarified,98 with evidence in favor63 and against3 their neuroprotective role. THE USE OF ARBS FOR NEUROPROTECTION IN CLINICAL SETTINGS

SV is supported by the Partners in Research Program, Georgetown University Medical Center (GX4002705) and by the Department of Neurosciences, Georgetown University Medical Center. JMS is supported by the Partners in Research Program, Georgetown University Medical Center (GX4002705) and by the Department of Pharmacology and Physiology, Georgetown University Medical Center. DISCLOSURE

The authors declared no conflicts of interest. References 1. Ismail H, Mitchell R, McFarlane SI, Makaryus AN. Pleiotropic effects of inhibitors of the RAAS in the diabetic population: above and beyond blood pressure lowering. Curr Diab Rep 2010; 10:32–36. 2. Zanchetti A, Elmfeldt D. Findings and implications of the Study on COgnition and Prognosis in the Elderly (SCOPE)–a review. Blood Press 2006; 15:71–79. 3. Saavedra JM. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 2012; 123:567–590. 4. Nelson L, Gard P, Tabet N. Hypertension and inflammation in Alzheimer’s disease: close partners in disease development and progression! J Alzheimers Dis 2014; 41:331–343. 5. Richardson C, Nilforooshan R, Gard PR, Weaving G, Tabet N. Impaired renal function and biomarkers of vascular disease in Alzheimer’s disease. Curr Alzheimer Res 2014; 11:253–258. 6. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol 2013; 24:353–363. 7. Hasnain M, Victor R, Vieweg W. Possible role of vascular risk factors in Alzheimer’s disease and vascular dementia. Curr Pharm Des March 14, 2014 (Epub ahead of print). 8. Pelisch N, Hosomi N, Mori H, Masaki T, Nishiyama A. RAS inhibition attenuates cognitive impairment by reducing blood- brain barrier permeability in hypertensive subjects. Curr Hypertens Rev 2013; 9:93–98. 9. Saavedra JM, Sánchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. Psychoneuroendocrinology 2011; 36:1–18. 10. Saavedra JM. Brain and pituitary angiotensin. Endocr Rev 1992; 13:329–380. 11. Zhou J, Pavel J, Macova M, Yu ZX, Imboden H, Ge L, Nishioku T, Dou J, Delgiacco E, Saavedra JM. AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats. Stroke 2006; 37:1271–1276. 12. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L. Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Invest 2010; 120:2782–2794. 13. Batenburg WW, Danser AH. (Pro)renin and its receptors: pathophysiological implications. Clin Sci (Lond) 2012; 123:121–133. 14. Ferrario CM, Ahmad S, Nagata S, Simington SW, Varagic J, Kon N, Dell’italia LJ. An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond) 2014; 126:461–469. 15. Horiuchi M, Iwanami J, Mogi M. Regulation of angiotensin II receptors beyond the classical pathway. Clin Sci (Lond) 2012; 123:193–203. 16. Kumar R, Thomas CM, Yong QC, Chen W, Baker KM. The intracrine renin-angiotensin system. Clin Sci (Lond) 2012; 123:273–284. 17. Saavedra JM. Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders. Cell Mol Neurobiol 2012; 32:667–681. 18. Michel MC, Foster C, Brunner HR, Liu L. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev 2013; 65:809–848. 19. Noda A, Fushiki H, Murakami Y, Sasaki H, Miyoshi S, Kakuta H, Nishimura S. Brain penetration of telmisartan, a unique centrally

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Several factors make the use of ARBs for the treatment of brain disorders a promising avenue. ARBs are widely used for the treatment of cardiovascular and metabolic diseases and exhibit excellent safety profiles. In normotensive subjects, these compounds do not significantly lower blood pressure, and initial reports of increased cancer incidence after ARB administration have been totally refuted.99 Additionally, ARBs ameliorate major injury mechanisms also contributing to brain disorders (Figure  4). In addition, there are strong pre-clinical data initial clinical reports and epidemiological studies supporting testing ARBs in controlled clinical trials. We propose a number of studies to further consider ARB repurposing for the treatment of brain disorders. These studies are feasible and may be immediately initiated. First, it is important to fully identify the most promising ARB for future clinical use, to advance in the understanding of the molecular mechanisms of ARB neuroprotection, and to perform additional epidemiological research. However, repurposing ARBs for the actual treatment of brain disorders faces several major obstacles. For example, for Alzheimer’s disease, there is a long track record of negative phase III studies for many candidate therapeutics effective in preclinical trials. Contributing factors include failure of rodent models of disease to fully represent the human condition and testing promising compounds only during the late stages of the disease, when brain damage is permanent and unlikely to be reversed. To overcome these obstacles, it is necessary to consider the development and characteristics of this brain disorder. For example, controlled studies must include groups of patients experiencing only mild cognitive impairment. Individuals carrying Alzheimer’s disease gene mutations and/or characteristic biomarker profiles, but not yet showing detectable cognitive loss are the best population to examine. Most currently available ARBs are or will soon be off patent, discouraging the Pharma industry from funding expensive intervention trials. Notwithstanding, there is a recent phase II, randomized, open label proof of concept study in progress, funded by the Canadian Government, to test telmisartan in hypertensive patients with mild to moderate Alzheimer’s disease http://clinicaltrials.gov/ct2/show/NCT0 2085265?term=sartans+and+alzheimer&rank=1. Given the major potential therapeutic benefit, it is possible that the National Institute on Aging may consider funding such trials. The evidence outlined in this review strongly supports testing ARBs for the treatment of a large number of brain disorders. If beneficial effects are confirmed in controlled clinical trials, repurposing these Food and Drug Administration (FDA)-approved, safe compounds for the treatment of brain disorders leading to cell injury may have an immediate translational impact, since to date there is no effective and safe way to protect neuronal tissue from disease.100

Acknowledgments

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