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Angiotensin II AT1 Receptor Blockers Ameliorate Inflammatory Stress: A Beneficial Effect for the Treatment of Brain Disorders

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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 AT1 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.

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References

  • Allen AM, MacGregor DP, McKinley MJ, Mendelsohn FA (1999) Angiotensin II receptors in the human brain. Regul Pept 79:1–7

    Article  PubMed  CAS  Google Scholar 

  • Anderson C (2010) More indirect evidence of potential neuroprotective benefits of Angiotensin receptor blockers. J Hypertens 28:429

    Article  PubMed  CAS  Google Scholar 

  • Ando H, Zhou J, Macova M, Imboden H, Saavedra JM (2004) Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke 35:1726–1731

    Article  PubMed  CAS  Google Scholar 

  • Anisman H (2009) Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci 34:4–20

    PubMed  Google Scholar 

  • Armando I, Carranza A, Nishimura Y, Hoe KL, Barontini M, Terrón JA, Falcón-Neri A, Ito T, Juorio AV, Saavedra JM (2001) Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation stress. Endocrinology 142:3880–3889

    Article  PubMed  CAS  Google Scholar 

  • Armando I, Volpi S, Aguilera G, Saavedra JM (2007) Angiotensin II AT1 receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress. Brain Res 1142:92–99

    Article  PubMed  CAS  Google Scholar 

  • Bader M (2010) Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Ann Rev Pharm Tox 50:439–465

    Article  CAS  Google Scholar 

  • Baiardi G, Bregonzio C, Jezova M, Armando I, Saavedra JM (2004) Angiotensin II AT1 receptor blockade prolongs the lifespan of spontaneously hypertensive rats and reduces stress-induced release of catecholamines, glucocorticoids, and vasopressin. Ann N Y Acad Sci 1018:131–136

    Article  PubMed  CAS  Google Scholar 

  • Barra S, Vitagliano A, Cuomo V, Vitagliano G, Gaeta G (2009) Vascular and metabolic effects of angiotensin II receptor blockers. Exp Opin Pharmacother 10:173–189

    Article  CAS  Google Scholar 

  • Benicky J, Sánchez-Lemus E, Pavel J, Saavedra JM (2009) Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol 29:781–792

    Article  PubMed  CAS  Google Scholar 

  • Benicky J, Sánchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, Leng Y, Chuang DM, Saavedra JM (2011) Angiotensin II AT(1) receptor blockade ameliorates brain inflammation. Neuropsychopharmacology 36:857–870

    Article  PubMed  CAS  Google Scholar 

  • Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119:524–530

    Article  PubMed  CAS  Google Scholar 

  • Braszko JJ, Karwowska-Polecka W, Halicka D, Gard PR (2003) Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol 14:323–343

    Article  PubMed  CAS  Google Scholar 

  • Bravo JA, Dinan TG, Cryan JF (2011) Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders. Int J Neuropsychopharmacol 14:666–683

    Article  PubMed  CAS  Google Scholar 

  • Bregonzio C, Armando I, Ando H, Jezova M, Baiardi G, Saavedra JM (2003) Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury. Am J Physiol Gastrointest Liver Physiol 285:G414–G423

    PubMed  CAS  Google Scholar 

  • Bregonzio C, Seltzer A, Armando I, Pavel J, Saavedra JM (2008) Angiotensin II AT(1) receptor blockade selectively enhances brain AT(2) receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats. Stress 11:457–466 (erratum in Stress 12:95, 2009)

    Google Scholar 

  • Castrén E, Saavedra JM (1988) Repeated stress increases the density of Angiotensin II binding sites in rat paraventricular nucleus and subfornical organ. Endocrinology 122:370–372

    Article  PubMed  Google Scholar 

  • Chrysant SG (2006) Clinical experience with the use of Angiotensin receptor blockers in patients with cardiovascular, cerebrovascular and renal diseases. Curr Clin Pharmacol 1:139–146

    Article  PubMed  CAS  Google Scholar 

  • Conner KR, Payne VS, Forbes ME, Robbins ME, Riddle DR (2010) Effects of the AT1 receptor antagonist L-158, 809 on microglia and neurogenesis after fractionated whole-brain irradiation. Radiat Res 173:49–61

    Article  PubMed  CAS  Google Scholar 

  • Dantzer R, Bluthé RM, Gheusi G, Cremona S, Layé S, Parnet P, Kelley KW (1998) Molecular basis of sickness behavior. Ann N Y Acad Sci 856:132–138

    Article  PubMed  CAS  Google Scholar 

  • Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  PubMed  CAS  Google Scholar 

  • de Gasparo M, Siragy HM (1999) The AT2 receptor: fact, fancy and fantasy. Regul Pept 81:11–24

    Article  PubMed  Google Scholar 

  • Devereux RB, Dahlöf B (2007) Potential mechanisms of stroke benefit favoring losartan in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Curr Med Res Opin 23:443–457

    Article  PubMed  CAS  Google Scholar 

  • Domschke K, Zwanzger P (2008) GABAergic and endocannabinoid dysfunction in anxiety—future therapeutic targets? Curr Pharm Des 14:3508–3517

    Article  PubMed  CAS  Google Scholar 

  • Editorial (2007) Ensuring drug safety: lessons from the thiazolidinediones. Lancet 370:1101

    Article  Google Scholar 

  • Edwards E, King JA, Fray JC (1999) Increased basal activity of the HPA axis and renin-angiotensin system in congenital learned helpless rats exposed to stress early in development. Int J Dev Neurosci 17:805–812

    Article  PubMed  CAS  Google Scholar 

  • Fogari R, Zoppi A (2004) Effect of antihypertensive agents on quality of life in the elderly. Drugs Aging 21:377–393

    Article  PubMed  CAS  Google Scholar 

  • Gard PR, Haigh SJ, Cambursano PT, Warrington CA (2001) Strain differences in the anxiolytic effects of losartan in the mouse. Pharmacol Biochem Behav 69:35–40

    Article  PubMed  CAS  Google Scholar 

  • Grammatopoulos TN, Jones SM, Ahmadi FA, Hoover BR, Snell LD, Skoch J, Jhaveri VV, Poczobutt AM, Weyhenmeyer JA, Zawada WM (2007) Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra. Mol Neurodegener 2:1

    Article  PubMed  Google Scholar 

  • Guha M, Mackman N (2001) LPS induction of gene expression in human monocytes. Cell Signal 13:85–94

    Article  PubMed  CAS  Google Scholar 

  • Hallevi H, Hazan-Halevy I, Paran E (2007) Modification of neutrophils adhesion to human endothelial cell line in acute ischemic stroke by dipyridamole and candesartan. Eur J Neurol 14:1002–1007

    Article  PubMed  CAS  Google Scholar 

  • Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155

    Article  PubMed  Google Scholar 

  • Hertzman M, Adler LW, Arling B, Kern M (2005) Lisinopril may augment antidepressant response. J Clin Psychopharmacol 25:618–620

    Article  PubMed  Google Scholar 

  • Ito T, Yamakawa H, Bregonzio C, Terrón JA, Falcón-Neri A, Saavedra JM (2002) Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist. Stroke 33:2297–2303

    Article  PubMed  CAS  Google Scholar 

  • Johnson AK, Grippo AJ (2006) Sadness and broken hearts: neurohumoral mechanisms and co-morbidity of ischemic heart disease and psychological depression. J Physiol Pharmacol 57(Suppl 11):5–29

    PubMed  Google Scholar 

  • Julius S, Nesbitt SD, Egan BM, Weber M, Michelson EL, Kaciroti N, Black HR, Grimm RH, Messerli FH, Oparil S, Schork A, Trial of Preventing Hypertension (TROPHY) Study Investigators (2006) Feasibility of treating prehypertension with an Angiotensin-receptor blocker. N Engl J Med 354:1–13

    Article  Google Scholar 

  • Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI, Kim JM, Kim M, Roh JK (2007) Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther 322:1051–1058

    Article  PubMed  CAS  Google Scholar 

  • Kaiser FC, Palmer GC, Wallace AV, Carr RD, Fraser-Rae L, Hallam C (1992) Antianxiety properties of the angiotensin II antagonist, DUP 753, in the rat using the elevated plus-maze. Neuroreport 3:922–924

    Article  PubMed  CAS  Google Scholar 

  • Kang YM, Ma Y, Zheng JP, Elks C, Sriramula S, Yang ZM, Francis J (2009) Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res 82:503–512

    Article  PubMed  CAS  Google Scholar 

  • Keck M, Holsboer F (2001) Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders. Peptides 22:835–844

    Article  PubMed  CAS  Google Scholar 

  • Kurihara T, Ozawa Y, Shinoda K, Nagai N, Inoue M, Oike Y, Tsubota K, Ishida S, Okano H (2006) Neuroprotective effects of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation. Invest Ophthalmol Vis Sci 47:5545–5552

    Article  PubMed  Google Scholar 

  • Lanz T, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L (2010) Angiotensin II sustains brain inflammation in mice via TGFb. J Clin Invest 120:2782–2794

    Article  PubMed  CAS  Google Scholar 

  • Larrayoz IM, Pang T, Benicky J, Pavel J, Sánchez-Lemus E, Saavedra JM (2009) Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes. J Hypertens 27:2365–2376

    Article  PubMed  CAS  Google Scholar 

  • Lee JW, Naidong W, Johnson T, Dzerk A, Miyabayashi T, Motohashi M (1995) Development and validation of column-switching high-performance liquid chromatographic methods for the determination of a potent AII receptor antagonist, TCV-116, and its metabolites in human serum and urine. J Chromatogr B Biomed Appl 670:287–298

    Article  PubMed  CAS  Google Scholar 

  • Leonard BE (2007) Inflammation, depression and dementia: are they connected? Neurochem Res 32:1749–1756

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Bains JS, Ferguson AV (1993) Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat. Brain Res Bull 30:33–39

    Article  PubMed  CAS  Google Scholar 

  • Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B (2010) Use of Angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 340:b5465

    Article  PubMed  Google Scholar 

  • Linz W, Heitsch H, Schölkens BA, Wiemer G (2000) Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats. Hypertension 35:908–913

    Article  PubMed  CAS  Google Scholar 

  • Lou M, Blume A, Zhao Y, Gohlke P, Deuschl G, Herdegen T, Culman J (2004) Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat. J Cereb Blood Flow Metab 24:536–547

    Article  PubMed  CAS  Google Scholar 

  • Lu GC, Cheng JW, Zhu KM, Ma XJ, Shen FM, Su DF (2009) A systematic review of Angiotensin receptor blockers in preventing stroke. Stroke 40:3876–3878

    Article  PubMed  CAS  Google Scholar 

  • Marchesi VT (2011) Alzheimer’s dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J 25:5–13

    Article  PubMed  CAS  Google Scholar 

  • Marchesi C, Paradis P, Schiffrin EL (2008) Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci 29:367–374

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto S, Shimodozono M, Miyata R, Kawahira K (2010) The Angiotensin II type 1 receptor antagonist olmesartan preserves cerebral blood flow and cerebrovascular reserve capacity, and accelerates rehabilitative outcomes in hypertensive patients with a history of stroke. Int J Neurosci 120:372–380

    Article  PubMed  CAS  Google Scholar 

  • McFarlane SI (2009) Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev CardiovascTher 7:1363–1371

    Article  CAS  Google Scholar 

  • Mertens B, Vanderheyden P, Michotte Y, Sarre S (2010) The role of the central renin-angiotensin system in Parkinson’s disease. J Renin Angiotensin Aldosterone Syst 11:49–56

    Article  PubMed  CAS  Google Scholar 

  • Miller G (2010) Is pharma running out of brainy ideas? Science 329:502–504

    Article  PubMed  CAS  Google Scholar 

  • Nagai N, Izumi-Nagai K, Oike Y, Koto T, Satofuka S, Ozawa Y, Yamashiro K, Inoue M, Tsubota K, Umezawa K, Ishida S (2007) Suppression of diabetes-induced retinal inflammation by blocking the Angiotensin II type 1 receptor or its downstream nuclear factor-kB pathway. Invest Ophthalmol Vis Sci 48:4342–4350

    Article  PubMed  Google Scholar 

  • Nasr SJ, Crayton JW, Agarwal B, Wendt B, Kora R (2011) Lower frequency of antidepressant use in patients on renin-angiotensin-aldosterone system modifying medications. Cell Mol Neurobiol 31:615–618

    Article  PubMed  Google Scholar 

  • Nimmo AJ, Vink R (2009) Recent patents in CNS drug discovery: the management of inflammation in the central nervous system. Recent Pat CNS Drug Discov 4:86–95

    Article  PubMed  CAS  Google Scholar 

  • Nishimura Y, Ito T, Saavedra JM (2000a) Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 31:2478–2486

    Article  PubMed  CAS  Google Scholar 

  • Nishimura Y, Ito T, Hoe K, Saavedra JM (2000b) Chronic peripheral administration of the angiotensin II AT(1) receptor antagonist candesartan blocks brain AT(1) receptors. Brain Res 871:29–38

    Article  PubMed  CAS  Google Scholar 

  • Ozacmak VH, Sayan H, Cetin A, Akyildiz-Igdem A (2007) AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem Res 32:1314–1321

    Article  PubMed  CAS  Google Scholar 

  • Papademetriou V, Farsang C, Elmfeldt D, Hofman A, Lithell H, Olofsson B, Skoog I, Trenkwalder P, Zanchetti A (2004) Study on Cognition and Prognosis in the Elderly study group. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol 44:1175–1180

    PubMed  CAS  Google Scholar 

  • Pascoe MC, Crewther SG, Carey LM, Crewther DP (2011) Inflammation and depression: why poststroke depression may be the norm and not the exception. Int J Stroke 6:128–135

    Article  PubMed  Google Scholar 

  • Pavlatou MG, Mastorakos G, Lekakis I, Liatis S, Vamvakou G, Zoumakis E, Papassotiriou I, Rabavilas AD, Katsilambros N, Chrousos GP (2008) Chronic administration of an angiotensin II receptor antagonist resets the hypothalamic-pituitary-adrenal (HPA) axis and improves the affect of patients with diabetes mellitus type 2: preliminary results. Stress 11:62–72

    Article  PubMed  CAS  Google Scholar 

  • Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz TV, Phillips LK, Goldstein MJ, Bhat R, Raine CS, Sobel RA, Steinman L (2009) Blocking Angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1-andTH17-mediated autoimmunity. Proc Natl Acad Sci USA 106:14948–14953

    Article  PubMed  CAS  Google Scholar 

  • Polidori C, Ciccocioppo R, Nisato D, Cazaubon C, Massi M (1998) Evaluation of the ability of irbesartan to cross the blood-brain barrier following acute intragastric treatment. Eur J Pharmacol 352:15–21

    Article  PubMed  CAS  Google Scholar 

  • Porrello ER, Delbridge LM, Thomas WG (2009) The angiotensin II type 2 (AT2) receptor: an enigmatic seven transmembrane receptor. Front Biosci 14:958–972

    Article  PubMed  CAS  Google Scholar 

  • Quan N, Banks WA (2007) Brain-immune communication pathways. Brain Behav Immun 21:727–735

    Article  PubMed  CAS  Google Scholar 

  • Rivest S (2010) Interactions between the immune and neuroendocrine systems. Prog Brain Res 181:43–53

    Article  PubMed  CAS  Google Scholar 

  • Robbins ME, Payne V, Tommasi E, Diz DI, Hsu FC, Brown WR, Wheeler KT, Olson J, Zhao W (2009) The AT1 receptor antagonist, L-158, 809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int. J Radiat Oncol Biol Phys 73:499–505

    Article  CAS  Google Scholar 

  • Rompe F, Unger T, Steckelings UM (2010) The angiotensin AT2 receptor in inflammation. Drug News Perspect 23:104–111

    Article  PubMed  CAS  Google Scholar 

  • Saavedra JM (1992) Brain and pituitary Angiotensin. Endocrin Rev 13:329–380

    CAS  Google Scholar 

  • Saavedra JM (2005) Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol 25:485–512

    Article  PubMed  CAS  Google Scholar 

  • Saavedra JM, Benicky J (2007) Brain and peripheral angiotensin II play a major role in stress. Stress 10:185–193

    Article  PubMed  CAS  Google Scholar 

  • Saavedra JM, Armando I, Bregonzio C, Juorio A, Macova M, Pavel J, Sanchez-Lemus E (2006) A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding. Neuropsychopharmacology. 31:1123–1134

    PubMed  CAS  Google Scholar 

  • Saavedra JM, Sánchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 36:1–18

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Lemus E, Murakami Y, Larrayoz-Roldan IM, Moughamian AJ, Pavel J, Nishioku T, Saavedra JM (2008) Angiotensin II AT1 receptor blockade decreases lipopolysaccharide-induced inflammation in the rat adrenal gland. Endocrinology 149:5177–5188

    Article  PubMed  CAS  Google Scholar 

  • Sánchez-Lemus E, Benicky J, Pavel J, Larrayoz IM, Zhou J, Baliova M, Nishioku T, Saavedra JM (2009a) Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen. Am J Physiol Regul Integr Comp Physiol 296:R1376–R1384

    Article  PubMed  Google Scholar 

  • Sánchez-Lemus E, Benicky J, Pavel J, Saavedra JM (2009b) In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland. Brain Behav Immun 23:945–957

    Article  PubMed  Google Scholar 

  • Savoia C, Schiffrin EL (2007) Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci (Lond) 112:375–384

    Article  CAS  Google Scholar 

  • Saxby BK, Harrington F, Wesnes KA, McKeith IG, Ford GA (2008) Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology 70:1858–1866

    Article  PubMed  CAS  Google Scholar 

  • Schwartz EA, Zhang WY, Karnik SK, Borwege S, Anand VR, Laine PS, Su Y, Reaven PD (2010) Nutrient modification of the innate immune response: a novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation. Arterioscler Thromb Vasc Biol 30:802–808

    Article  PubMed  CAS  Google Scholar 

  • Seltzer A, Bregonzio C, Armando I, Baiardi G, Saavedra JM (2004) Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats. Brain Res 1028:9–18

    Article  PubMed  CAS  Google Scholar 

  • Shekhar A, Johnson PL, Sajdyk TJ, Fitz SD, Keim SR, Kelley PE, Gehlert DR, DiMicco JA (2006) Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci 26:9205–9215

    Article  PubMed  CAS  Google Scholar 

  • Sironi L, Gelosa P, Guerrini U, Banfi C, Crippa V, Brioschi M, Gianazza E, Nobili E, Gianella A, de Gasparo M, Tremoli E (2004) Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall. J Pharmacol Exp Ther 311:989–995

    Article  PubMed  CAS  Google Scholar 

  • Skrbic R, Igic R (2009) Seven decades of angiotensin (1939–2009). Peptides 30:1945–1950

    Article  PubMed  CAS  Google Scholar 

  • Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A, Ufnal M, Zera T (2010) Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J Physiol Pharmacol 61:509–521

    PubMed  CAS  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  PubMed  CAS  Google Scholar 

  • Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–251

    PubMed  CAS  Google Scholar 

  • Tsukuda K, Mogi M, Iwanami J, Min LJ, Sakata A, Jing F, Iwai M, Horiuchi M (2009) Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation. Hypertension 54:782–787

    Article  PubMed  CAS  Google Scholar 

  • Tsutsumi K, Saavedra JM (1991) Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. Am J Physiol 261:R209–R216

    PubMed  CAS  Google Scholar 

  • Wang JM, Tan J, Leenen FH (2003) Central nervous system blockade by peripheral administration of AT1 receptor blockers. J Cardiovasc Pharmacol 41:593–599

    Article  PubMed  CAS  Google Scholar 

  • Weber MA (2005) Angiotensin-II receptor blockers for hypertension and heart failure: quality of life and outcomes. Manag Care Interface 18:47–54

    PubMed  Google Scholar 

  • Weinberg AJ, Zappe DH, Ashton M, Weinberg MS (2004) Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study. Am J Nephrol 24:340–345

    Article  PubMed  CAS  Google Scholar 

  • Xang G, Xi ZX, Wan Y, Wang H, Bi G (1993) Changes in circulating and tissue Angiotensin II during acute and chronic stress. Biol Signals 2:166–172

    Article  Google Scholar 

  • Yamakawa H, Jezova M, Ando H, Saavedra JM (2003) Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab 23:371–380

    Article  PubMed  CAS  Google Scholar 

  • Zanchetti A, Elmfeldt D (2006) Findings and implications of the Study on Cognition and Prognosis in the Elderly (SCOPE)—a review. Blood Press 15:71–79

    Article  PubMed  Google Scholar 

  • Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T (2010) Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171:852–858

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Ando H, Macova M, Dou J, Saavedra JM (2005) Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats. J Cereb Blood Flow Metab 25:878–886

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA.

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  1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Room 2D-57, Bethesda, MD, 20892, USA

    Juan M. Saavedra

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Saavedra, J.M. Angiotensin II AT1 Receptor Blockers Ameliorate Inflammatory Stress: A Beneficial Effect for the Treatment of Brain Disorders. Cell Mol Neurobiol 32, 667–681 (2012). https://doi.org/10.1007/s10571-011-9754-6

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