Pharmacopsychiatry 2017; 50(06): 233-247
DOI: 10.1055/s-0043-112345
Review
© Georg Thieme Verlag KG Stuttgart · New York

Validation of Brain Angiotensin System Blockade as a Novel Drug Target in Pharmacological Treatment of Neuropsychiatric Disorders

Dominik Wincewicz
1   Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland
2   Department of Psychiatry, Medical University of Bialystok, Poland
,
Jan J. Braszko
1   Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland
› Author Affiliations
Further Information

Publication History

received 16 September 2016
revised 08 May 2017

accepted 18 May 2017

Publication Date:
22 June 2017 (online)

Abstract

Retreat in psychiatric drug development results in innovative medication decline that might be at least partially overcome by adjunct therapy. New evidence from clinical studies has shown a possible role for brain Renin-Angiotensin System (RAS) in both affective and psychotic disorders. Simultaneously, rapidly accumulating data from basic studies indicate effectiveness of central RAS blockade in much broader range of neuropsychiatric disease. Recent findings implicate brain RAS, especially Angiotensin II (Ang II), in neural pathophysiology of mental disorders through neuroendocrine modulation and effects on neurotransmitter release, mostly noradrenaline, acetylcholine and dopamine. The potential effects of angiotensin-converting-enzyme (ACE) inhibition and angiotensin type 1 receptor (AT1R) blockade on treatment of mental disorders are a matter of considerable interest. This review describes involvement of brain RAS in pathophysiology of neuropsychiatric disorders and an intriguing possibilities of improvement in pharmacological treatment outcome, where using angiotensin-converting-enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB), goes beyond blood pressure control.

 
  • References

  • 1 O'Donnell P, Ehlers MD. Opportunities for new drug development in psychiatry: a glass half-full. JAMA Psychiatry 2015; 72: 1067-1068
  • 2 Scannell JW, Bosley J. When quality beats quantity: decision theory, drug discovery, and the reproducibility crisis. PLoS One 2016; 11: e0147215
  • 3 Global Burden of Disease (GBD). World Health Organization 2012;
  • 4 Bloom DE, Cafiero ET, Jané-Llopis E. et al. The global economic burden of non-communicable diseases. Geneva: World Economic Forum; 2011
  • 5 Wright JW, Harding JW. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers. Arch 2013; 465: 133-151
  • 6 Nasr SJ, Crayton JW, Agarwal B. et al. Lower frequency of antidepressant use in patients on renin-angiotensin-aldosterone system modifying medications. Cell Mol Neurobiol 2011; 31: 615-618
  • 7 Murck H, Schüssler P, Steiger A. Renin-angiotensin-aldosterone system: the forgotten stress hormone system: relationship to depression and sleep. Pharmacopsychiatry 2012; 45: 83-95
  • 8 Hayes LH, Sawa A. Angiotensin signaling in the development and pathology of immune-associated psychosis. Schizophr Bull 2015; 41 (Suppl. 01) S4
  • 9 Saavedra JM. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 2012; 123: 567-590
  • 10 Anderson C. More indirect evidence of potential neuroprotective benefits of Angiotensin receptor blockers. J Hypertens 2010; 28: 429
  • 11 Li NC, Lee A, Whitmer RA. et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010; 340: b5465
  • 12 Pavlatou MG, Mastorakos G, Lekakis I. et al. 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 2008; 11: 62-72
  • 13 Fogari R, Zoppi A. Effect of antihypertensive agents on quality of life in the elderly. Drugs Aging 2004; 21: 377-393
  • 14 Braszko JJ, Wincewicz D, Jakubów P. Candesartan prevents impairment of recall caused by repeated stress in rats. Psychopharmacology (Berl) 2013; 225: 421-428
  • 15 Wincewicz D, Braszko JJ. Telmisartan attenuates cognitive impairment caused by chronic stress in rats. Pharmacol Rep 2014; 66: 436-441
  • 16 Wincewicz D, Braszko JJ. Angiotensin II AT1 receptor blockade by telmisartan reduces impairment of spatial maze performance induced by both acute and chronic stress. J Renin Angiotensin Aldosterone Syst 2015; 16: 495-505
  • 17 Wincewicz D, Juchniewicz A, Waszkiewicz N. et al. Angiotensin II type 1 receptor blockade by telmisartan prevents stress-induced impairment of memory via HPA axis deactivation and up-regulation of brain-derived neurotrophic factor gene expression. Pharmacol Biochem Behav 2016; 148: 108-118
  • 18 Erhardt A, Ising M, Unschuld PG. et al. Regulation of the hypothalamic–pituitary–adrenocortical system in patients with panic disorder. Neuropsychopharmacology 2006; 31: 2515-2522
  • 19 Corcoran C, Mujica-Parodi L, Yale S. et al. Could stress cause psychosis in individuals vulnerable to schizophrenia?. CNS Spectr 2002; 7: 33-38 41-42
  • 20 Lo Sauro C, Ravaldi C, Cabras PL. et al. Stress, hypothalamic-pituitary-adrenal axis and eating disorders. Neuropsychobiology 2008; 57: 95-115
  • 21 Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000; 48: 755-765
  • 22 Popoli M, Yan Z, McEwen BS. et al. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2011; 13: 22-37
  • 23 Chetty S, Friedman AR, Taravosh-Lahn K. et al. Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus. Mol Psychiatry 2014; 19: 1275-1283
  • 24 Keller PA, McCluskey A, Morgan J. et al. The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments. Arch Pharm (Weinheim) 2006; 339: 346-355
  • 25 Yang G, Wan Y, Zhu Y. Angiotensin II--an important stress hormone. Biol Signals 1996; 5: 1-8
  • 26 Bregonzio C, Seltzer A, Armando I. et al. 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 2008; 6: 457-466
  • 27 Israel A, Stromberg C, Tsutsumi K. et al. Angiotensin II receptor subtypes and phosphoinositide hydrolysis in rat adrenal medulla. Brain Res Bull 1995; 38: 441-446
  • 28 Von Bohlen und Halbach O, Albrecht D. Mapping of angiotensin AT1 receptors in the rat limbic system. Regul Pept 1998; 78: 51-56
  • 29 Lenkei Z, Palkovits M, Corvol P. et al. Distribution of angiotensin type-1 receptor messenger RNA expression in the adult rat brain. Neuroscience 1998; 82: 827-841
  • 30 Schulkin J. Angst and the amygdala. Dialogues Clin Neurosci 2006; 8: 407-416
  • 31 Aguilera G, Kiss A, Luo X. Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. J Neuroendocrinol 1995; 7: 775-783
  • 32 Oldfield BJ, Davern PJ, Giles ME. et al. Efferent neural projections of angiotensin receptor (AT1) expressing neurons in the hypothalamic paraventricular nucleus of the rat. J Neuroendocrinol 2001; 13: 139-146
  • 33 Wright JW, Harding JW. Brain angiotensin receptor subtypes in the control of physiological and behavioral responses. Neurosci Biobehav Rev 1994; 18: 21-53
  • 34 Cierco M, Israel A. Role of angiotensin AT1 receptor in the cardiovascular response to footshock. Eur J Pharmacol 1994; 251: 103-106
  • 35 Kregel KC, Stauss H, Unger T. Modulation of autonomic nervous system adjustments to heat stress by central ANG II receptor antagonism. Am J Physiol 1994; 266: R1985-R1991
  • 36 Saiki Y, Watanabe T, Tan N. et al. Role of central ANGII receptors in stress-induced cardiovascular and hyperthermic responses in rats. Am J Physiol 1997; 272: R26-R33
  • 37 Armando I, Carranza A, Nishimura Y. et al. Peripheral administration of an angiotensin I AT1 receptor antagonist decreases the hypothalamic-pituitary-adrenal response to stress. Endocrinology 2001; 142: 3880-3889
  • 38 Saavedra JM, Ando H, Armando I. et al. Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists. Regul Pept 2005; 128: 227-238
  • 39 Zhenfeng Z, Huilan S, Junya J. et al. A systematic review and meta-analysis of candesartan and losartan in the management of essential hypertension. J Renin Angiotensin Aldosterone Syst 2011; 12: 365-374
  • 40 Raasch W, Wittmershaus C, Dendorfer A. et al. Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats. Endocrinology 2006; 147: 3539-3546
  • 41 Steckelings UM, Kaschina E, Unger T. The AT2 receptor--a matter of love and hate. Peptides 2005; 26: 1401-1409
  • 42 Steckelings UM, Rompe F, Kaschina E. et al. The past, present and future of angiotensin II type 2 receptor stimulation. J Renin Angiotensin Aldosterone Syst 2010; 11: 67-73
  • 43 Li J, Culman J, Hörtnagl H. et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J 2005; 19: 617-619
  • 44 Steckelings UM, Unger T. Angiotensin II type 2 receptor agonists--where should they be applied?. Expert Opin Investig Drugs 2012; 21: 763-766
  • 45 Schinke M, Baltatu O, Böhm M. et al. Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc Natl Acad Sci USA 1999; 96: 3975-3980
  • 46 Foulquier S, Steckelings UM, Unger T. Impact of the AT(2) receptor agonist C21 on blood pressure and beyond. Curr Hypertens Rep 2012; 14: 403-409
  • 47 Seltzer A, Bregonzio C, Armando I. et al. Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats. Brain Res 2004; 1028: 9-18
  • 48 McCarthy CA, Vinh A, Miller AA. et al. Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats. PLoS One 2014; 9: e95762
  • 49 Fouda AY, Pillai B, Dhandapani KM. et al. Role of interleukin-10 in the neuroprotective effect of the angiotensin type 2 receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol 2017; 799: 128-134
  • 50 Wright JW, Harding JW. The angiotensin AT4 receptor subtype as a target for the treatment of memory dysfunction associated with Alzheimer's disease. J Renin Angiotensin Aldosterone Syst 2008; 9: 226-237
  • 51 Yasuda N, Miura S, Akazawa H. et al. Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation. EMBO Rep 2008; 9: 179-186
  • 52 Bondi CO, Rodriguez G, Gould GG. et al. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 2008; 33: 320-331
  • 53 Oveisgharan S, Hachinski V. Hypertension, executive dysfunction, and progression to dementia: the Canadian study of health and aging. Arch Neurol 2010; 67: 187-192
  • 54 Ciobica A, Bild W, Hritcu L. et al. Brain renin-angiotensin system in cognitive function: pre-clinical findings and implications for prevention and treatment of dementia. Acta Neurol Belg 2009; 109: 171-180
  • 55 Kang HG, Mahoney DF, Hoenig H. et al. Center for Integration of Medicine and Innovative Technology Working Group on Advanced Approaches to Physiologic Monitoring for the Aged. In situ monitoring of health in older adults: technologies and issues. J Am Geriatr Soc 2010; 58: 1579-1586
  • 56 Hajjar I, Hart M, Chen YL. et al. Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med 2012; 172: 442-444
  • 57 Li NC, Lee A, Whitmer RA. et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010; 340: b5465
  • 58 Kume K, Hanyu H, Sakurai H. et al. Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease. Geriatr Gerontol Int 2012; 12: 207-214
  • 59 Black SE. Telmisartan vs. perindopril in hypertensive mild-moderate Alzheimer’s disease patients (SARTAN-AD). Alzheimer’s Drug Discovery Foundation. www.clinicalTrials.gov Identifier: NCT02085265
  • 60 Horiuchi M, Mogi M, Iwai M. The angiotensin II type 2 receptor in the brain. J Renin Angiotensin Aldosterone Syst 2010; 11: 1-6
  • 61 Ongali B, Nicolakakis N, Tong XK. et al. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis 2014; 68: 126-136
  • 62 Kurata T, Lukic V, Kozuki M. et al. Long-term effect of telmisartan on Alzheimer's amyloid genesis in SHR-SR after tMCAO. Transl Stroke Res 2015; 6: 107-115
  • 63 Torika N, Asraf K, Danon A. et al. Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One 2016; 11: e0155823
  • 64 Pelisch N, Hosomi N, Ueno M. et al. Blockade of AT1 receptors protects the blood–brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats. Am J Hypertens 2011; 24: 362-368
  • 65 Braszko JJ, Kupryszewski G, Witczuk B. et al. Angiotensin II (3-8)-hexapeptide affects motor activity, performance of passive avoidance, and a conditioned avoidance response in rats. Neuroscience 1988; 27: 777-783
  • 66 Albiston AL, Allen AM, Mendelsohn FA. et al. Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats. Neuroscience 2004; 124: 341-349
  • 67 Braszko JJ, Walesiuk A, Wielgat P. Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV. J Renin Angiotensin Aldosterone Syst 2006; 7: 168-174
  • 68 Vanderheyden PM. From angiotensin IV binding site to AT4 receptor. Mol Cell Endocrinol 2009; 302: 159-166
  • 69 Lee J, Chai SY, Mendelsohn FA. et al. Potentiation of cholinergic transmission in the rat hippocampus by angiotensin IV and LVV-hemorphin-7. Neuropharmacol 2001; 40: 618-623
  • 70 Braszko JJ. Involvement of D1 dopamine receptors in the cognitive effects of angiotensin IV and des-Phe6 angiotensin IV. Peptides 2004; 25: 1195-1203
  • 71 Hamanoue M, Takemoto N, Matsumoto K. et al. Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro. J Neurosci Res 1996; 43: 554-564
  • 72 Kawas LH, McCoy AT, Yamamoto BJ. et al. Development of angiotensin IV analogs as hepatocyte growth factor/Met modifiers. J Pharmacol Exp Ther 2012; 340: 539-548
  • 73 Zubenko GS, Nixon RA. Mood-elevating effect of captopril in depressed patients. Am J Psychiatry 1984; 141: 110-111
  • 74 Deicken RF. Captopril treatment of depression. Biol Psychiatry 1986; 21: 1425-1428
  • 75 Germain L, Chouinard G. Treatment of recurrent unipolar major depression with captopril. Biol Psychiatry 1988; 23: 637-641
  • 76 Germain L, Chouinard G. Captopril treatment of major depression with serial measurements of blood cortisol concentrations. Biol Psychiatry 1989; 25: 489-493
  • 77 Braszko JJ, Karwowska-Polecka W, Halicka D. et al. Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol 2003; 14: 323-343
  • 78 Nasr SJ, Crayton JW, Agarwal B. et al. Lower frequency of antidepressant use in patients on renin-angiotensin-aldosterone system modifying medications. Cell Mol Neurobiol 2011; 31: 615-618
  • 79 Ancelin ML, Carrière I, Scali J. et al. Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression. Transl Psychiatry 2013; 3: e322
  • 80 Saab YB, Gard PR, Yeoman MS. et al. Renin-angiotensin-system gene polymorphisms and depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1113-1118
  • 81 Kucukali CI, Aydin M, Ozkok E. et al. Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. Psychiatr Genet 2010; 20: 14-19
  • 82 Fudalej S, Fudalej M, Kostrzewa G. et al. Angiotensin-converting enzyme polymorphism and completed suicide: an association in Caucasians and evidence for a link with a method of self-injury. Neuropsychobiology 2009; 59: 151-158
  • 83 Baghai TC, Binder EB, Schule C. et al. Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity, and hypercortisolism. Mol Psychiatry 2006; 11: 1003-1015
  • 84 Kondo DG, Speer MC, Krishnan KR. et al. Association of AGTR1 with 18-month treatment outcome in late-life depression. Am J Geriatr Psychiatry 2007; 15: 564-572
  • 85 Scherrer JF, Hong X, Bucholz KK. et al. A twin study of depression symptoms, hypertension, and heart disease in middle-aged men. Psychosom Med 2003; 65: 548-557
  • 86 Okuyama S, Sakagawa T, Sugiyama F. et al. Reduction of depressive-like behavior in mice lacking angiotensinogen. Neurosci Lett 1999; 261: 167-170
  • 87 Gard PR, Mandy A, Sutcliffe MA. Evidence of a possible role of altered angiotensin function in the treatment, but not etiology, of depression. Biol Psychiatry 1999; 45: 1030-1034
  • 88 Ferguson AV, Washburn DL, Latchford KJ. Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med (Maywood) 2001; 226: 85-96
  • 89 McKinley MJ, Albiston AL, Allen AM. et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003; 35: 901-918
  • 90 Fabiani ME, Sourial M, Thomas WG. et al. enhances noradrenaline release from sympathetic nerves of the rat prostate via a novel angiotensin receptor: implications for the pathophysiology of benign prostatic hyperplasia. J Endocrinol 2001; 171: 97-108
  • 91 Vatta MS, Bianciotti LG, Locatelli AS. et al. Monophasic and biphasic effects of angiotensin II and III on norepinephrine uptake and release in rat adrenal medulla. Can J Physiol Pharmacol 1992; 70: 821-825
  • 92 Grupp LA, Perlanski E, Stewart RB. Attenuation of alcohol intake by a serotonin uptake inhibitor: evidence for mediation through the renin-angiotensin system. Pharmacol Biochem Behav 1988; 30: 823-837
  • 93 Tanaka J, Kariya K, Nomura M. Angiotensin II reduces serotonin release in the rat subfornical organ area. Peptides 2003; 24: 881-887
  • 94 Jenkins TA. Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats. Neurosci Lett 2008; 444: 186-189
  • 95 Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 2010; 70: 289-297
  • 96 Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22-34
  • 97 Sánchez-Lemus E, Benicky J, Pavel J. et al. In vivo angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland. Brain Behav Immun 2009; 23: 945-957
  • 98 Kono S, Kurata T, Sato K. et al. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. J Stroke Cerebrovasc Dis 2015; 24: 537-547
  • 99 Xu Y, Xu Y, Wang Y. et al. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun 2015; 50: 298-313
  • 100 Bhat SA, Goel R, Shukla R. et al. Angiotensin receptor blockade modulates NFκB and STAT3 signaling and inhibits glial activation and neuroinflammation better than angiotensin-converting enzyme inhibition. Mol Neurobiol 2016; 53: 6950-6967
  • 101 Liu F, Havens J, Yu Q. et al. The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress. Int J Physiol Pathophysiol Pharmacol 2012; 4: 28-35
  • 102 Duric V, Banasr M, Licznerski P. et al. A negative regulator of MAP kinase causes depressive behavior. Nat Med 2010; 16: 1328-1332
  • 103 Lam RW, Levitan RD. Pathophysiology of seasonal affective disorder: a review. J Psychiatry Neurosci 2000; 25: 469-480
  • 104 Baltatu O, Lippoldt A, Hansson A. et al. Local renin-angiotensin system in the pineal gland. Brain Res Mol Brain Res 1998; 54: 237-242
  • 105 Campos LA, Cipolla-Neto J, Amaral FG. et al. The angiotensin-melatonin axis. Int J Hypertens 2013; 2013: 521783
  • 106 Baltatu O, Afeche SC, José dos Santos SH. et al. Locally synthesized angiotensin modulates pineal melatonin generation. J Neurochem 2002; 80: 328-334
  • 107 Ishigaki S, Ohashi N, Isobe S. et al. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease. Clin Exp Nephrol 2016; 20: 878-884
  • 108 Corcoran C, Mujica-Parodi L, Yale S. et al. Could stress cause psychosis in individuals vulnerable to schizophrenia?. CNS Spectr 2002; 7: 33-38 41–2
  • 109 Gejman PV, Sanders AR, Duan J. The role of genetics in the etiology of schizophrenia. Psychiatr Clin North Am 2010; 33: 35-66
  • 110 Gadelha A, Yonamine CM, Ota VK. et al. ACE I/D genotype-related Increase in ACE plasma enzymatic activity is a better predictor of Schizophrenia diagnosis than ACE I/D genotypes alone. Schizophr Res 2015; 164: 109-114
  • 111 Song GG, Lee YH. The insertion/deletion polymorphism in the angiotensin-converting enzyme and susceptibility to schizophrenia or Parkinson's disease: A meta-analysis. J Renin Angiotensin Aldosterone Syst 2015; 16: 434-442
  • 112 Kucukali CI, Aydin M, Ozkok E. et al. Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. Psychiatr Genet 2010; 20: 14-19
  • 113 Thakur KS, Prakash A, Bisht R. et al. Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat. J Renin Angiotensin Aldosterone Syst 2015; 16: 917-929
  • 114 Martin S, Markus MA, Morris BJ. et al. Does angiotensin interact with dopaminergic mechanisms in the brain to modulate prepulse inhibition in mice?. Neuropharmacology 2008; 54: 399-404
  • 115 Brown DC, Steward LJ, Ge J. et al. Ability of angiotensin II to modulate striatal dopamine release via the AT1 receptor in vitro and in vivo. Br J Pharmacol 1996; 118: 414-420
  • 116 Gendron L, Payet MD, Gallo-Payet N. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. J Mol Endocrinol 2003; 31: 359-372
  • 117 Binder EB, Kinkead B, Owens MJ. et al. The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs. Biol Psychiatry 2001; 50: 856-872
  • 118 Tooney PA, Crawter VC, Chahl LA. Increased tachykinin NK(1) receptor immunoreactivity in the prefrontal cortex in schizophrenia. Biol Psychiatry 2001; 49: 523-527
  • 119 Arregui A, Mackay AV, Spokes EG. et al. Reduced activity of angiotensin-converting enzyme in basal ganglia in early onset schizophrenia. Psychol Med 1980; 10: 307-313
  • 120 Beckmann H, Saavedra JM, Gattaz WF. Low angiotensin-converting enzyme activity (kininase II) in cerebrospinal fluid of schizophrenics. Biol Psychiatry 1984; 19: 679-684
  • 121 Wahlbeck K, Rimon R, Fyhrquist F. Elevated angiotensin-converting enzyme (kininase II) in the cerebrospinal fluid of neuroleptic-treated schizophrenic patients. Schizophr Res 1993; 9: 77-82
  • 122 Wahlbeck K, Ahokas A, Miettinen K. et al. Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free patients with schizophrenia. Schizophr Bull 1998; 24: 391-397
  • 123 Baskan NM, Basaran A, Yenilmez C. et al. Investigation of association between angiotensin-converting enzyme gene insertion/deletion polymorphism frequency in Turkish patients with schizophrenia. Genet Test Mol Biomarkers 2010; 14: 753-757
  • 124 Gadelha A, Vendramini AM, Yonamine CM. et al. Convergent evidences from human and animal studies implicate angiotensin I-converting enzyme activity in cognitive performance in schizophrenia. Transl Psychiatry 2015; 5: e691
  • 125 Nasrallah HA. Metabolic findings from the CATIE trial and their relation to tolerability. CNS Spectr 2006; 11 (Suppl. 07) 32-39
  • 126 Clasen R, Schupp M, Foryst-Ludwig A. et al. PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension 2005; 46: 137-143
  • 127 Benson SC, Pershadsingh HA, Ho CI. et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004; 43: 993-1002
  • 128 Yamagishi S, Nakamura K, Matsui T. Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders. Curr Mol Med 2007; 7: 463-469
  • 129 Michel MC, Foster C, Brunner HR. et al. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev 2013; 65: 809-848
  • 130 Takagi H, Niwa M, Mizuno Y. et al. Telmisartan as a metabolic sartan: the first metaanalysis of randomized controlled trials in metabolic syndrome. J Am Soc Hypertens 2013; 7: 229-235
  • 131 Huang GZ, Tang YH, Wang BY. et al. Effects of telmisartan on insulin resistance and visceral fat distribution in Chinese hypertensive patients with obesity. Saudi Med J 2011; 32: 1017-1021
  • 132 Yamaguchi K, Tsutsumi E. The insulin sparing effect of telmisartan in a case of type 2 diabetes mellitus associated with schizophrenia under treatment of risperidone. Intern Med 2010; 49: 919-923
  • 133 Yamashita H, Yoda H, Kuroki N. et al. Angiotensin II type 1 receptor blockers improve insulin sensitivity in patients with schizophrenia being treated with olanzapine. Psychopharmacology (Berl) 2011; 213: 1-9
  • 134 Ginty AT, Carroll D, Roseboom TJ. et al. Depression and anxiety are associated with a diagnosis of hypertension 5 years later in a cohort of late middle-aged men and women. J Hum Hypertens 27: 187-190
  • 135 Suzman MM. Propranolol in the treatment of anxiety. Postgrad Med J 1976; 52 (Suppl. 04) 168-174
  • 136 Steenen SA, van Wijk AJ, van der Heijden GJ. et al. Propranolol for the treatment of anxiety disorders: Systematic review and meta-analysis. J Psychopharmacol 2016; 30: 128-139
  • 137 Armando I, Carranza A, Nishimura Y. et al. Peripheral administration of an angiotensin II AT1 receptor antagonist decreases the hypothalamic–pituitary–adrenal response to stress. Endocrinology 2001; 142: 3880-3889
  • 138 Krsková L, Vrabcová M, Talarovicová A. et al. Influence of up-regulated renin-angiotensin system on the exploration, anxiety-related behavior and object recognition. Acta Biol Hung 2009; 60: 369-383
  • 139 López LH, Caif F, García S. et al. Anxiolytic-like effect of losartan injected into amygdala of the acutely stressed rats. Pharmacol Rep 2012; 64: 54-63
  • 140 Marinzalda Mde L, Pérez PA, Gargiulo PA. et al. Fear-potentiated behaviour is modulated by central amygdala angiotensin II AT1 receptors stimulation. Biomed Res Int 2014; 2014: 183248
  • 141 Srinivasan J, Suresh B, Ramanathan M. Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats. Physiol Behav 2003; 78: 585-591
  • 142 Hein L, Barsh GS, Pratt RE. et al. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 1995; 377: 744-747
  • 143 Ichiki T, Labosky PA, Shiota C. et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 1995; 377: 748-750
  • 144 Braszko JJ, Kułakowska A, Winnicka MM. Effects of angiotensin II and its receptor antagonists on motor activity and anxiety in rats. J Physiol Pharmacol 2003; 2: 271-281
  • 145 Voigt JP, Hörtnagl H, Rex A. et al. Brain angiotensin and anxiety-related behavior: the transgenic rat TGR(ASrAOGEN)680. Brain Res 2005; 1046: 145-156
  • 146 Belcheva I, Georgiev V, Chobanova M. et al. Behavioral effects of angiotensin II microinjected into CA1 hippocampal area. Neuropeptides 1997; 31: 60-64
  • 147 Okuyama S, Sakagawa T, Chaki S. et al. Anxiety like behavior in mice lacking the angiotensin II type-2 receptor. Brain Res 1999; 821: 150-159
  • 148 Beyer CE, Dwyer JM, Platt BJ. et al. Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation. Psychopharmacology (Berl) 2010; 209: 303-311
  • 149 Pavel J, Benicky J, Murakami Y. et al. Peripherally administered angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo. Ann N Y Acad Sci 2008; 1148: 360-366
  • 150 Nutt DJ, Malizia AL. New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 2001; 179: 390-396
  • 151 Saavedra JM, Armando I, Bregonzio C. et al. A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding. Neuropsychopharmacology 2006; 31: 1123-1134
  • 152 Sánchez-Lemus E, Honda M, Saavedra JM. et al. AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress. Behav Brain Res 2012; 232: 84-92
  • 153 Khoury NM, Marvar PJ, Gillespie CF. et al. The renin-angiotensin pathway in posttraumatic stress disorder: angiotens inconverting enzyme inhibitors and angiotensin receptor blockers are associated with fewer traumatic stress symptoms. J Clin Psychiatry 2012; 73: 849-855
  • 154 Villapol S, Saavedra JM. Neuroprotective effects of angiotensin receptor blockers. Am J Hypertens 2015; 28: 289-299
  • 155 Benicky J, Sánchez-Lemus E, Honda M. et al. Angiotensin II AT1 receptor blockade ameliorates brain inflammation. Neuropsychopharmacology 2011; 36: 857-870
  • 156 Benicky J, Sánchez-Lemus E, Pavel J. et al. Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol 2009; 29: 781-792
  • 157 Danielyan L, Lourhmati A, Verleysdonk S. et al. Angiotensin receptor type 1 blockade in astroglia decreases hypoxia-induced cell damage and TNF alpha release. Neurochem Res 2007; 32: 1489-1498
  • 158 Pang T, Benicky J, Wang J. et al. Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes. J Hypertens 2012; 30: 87-96
  • 159 Pang T, Wang J, Benicky J. et al. Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 2012; 9: 102
  • 160 Sohn YI, Lee NJ, Chung A. et al. Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking. Biochem Biophys Res Commun 2013; 439: 464-470
  • 161 Noda A, Fushiki H, Murakami Y. et al. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques. Nucl Med Biol 2012; 39: 1232-1235
  • 162 Shimizu K, Takashima T, Yamane T. et al. Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3. Nucl Med Biol 2012; 39: 847-853
  • 163 Diener HC. Preventing stroke: the PRoFESS, ONTARGET, and TRANSCEND trial programs. J Hypertens Suppl 2009; 27: S31-S36
  • 164 Michalsen A, Wenzel RR, Mayer C. et al. Quality of life and psychosocial factors during treatment with antihypertensive drugs. A comparison of captopril and quinapril in geriatric patients. Herz 2001; 26: 468-476
  • 165 Muders F, Elsner D, Jandeleit K. et al. Chronic ACE inhibition by quinapril modulates central vasopressinergic system. Cardiovasc Res 1997; 34: 575-581
  • 166 Croog SH, Levine S, Testa MA. et al. The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986; 314: 1657-1664
  • 167 Testa MA, Anderson RB, Nackley JF. et al. Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. The Quality-of-Life Hypertension Study Group. N Engl J Med 1993; 328: 907-913
  • 168 Dengerink HA, Mead JD, Bertilson HS. Individual differences in response to alcohol. Vasoconstriction and vasodilation. J Stud Alchol 1978; 39: 12-18
  • 169 Cairns V, Keil U, Kleinbaum D. et al. Alcohol consumption as a risk factor for high blood pressure. Munich Blood Pressure Study. Hypertension 1984; 6: 124-131
  • 170 Grupp LA. The renin-angiotensin system: a multidimensional source of control over alcohol consumption. Alcohol Alcohol Suppl 1991; 1: 421-426
  • 171 Lingham T, Perlanski E, Grupp LA. Angiotensin converting enzyme inhibitors reduce alcohol consumption: some possible mechanisms and important conditions for its therapeutic use. Alcohol Clin Exp Res 1990; 14: 92-99
  • 172 Wayner MJ, Polan-Curtain JL, Chiu SC. et al. Losartan reduces ethanol intoxication in the rat. Alcohol 1994; 11: 343-346
  • 173 Rose AK, Shaw SG, Prendergast MA. et al. The importance of glucocorticoids in alcohol dependence and neurotoxicity. Alcohol Clin Exp Res 2010; 34: 2011-2018
  • 174 Newton TF, De La Garza 2nd R, Grasing K. The angiotensin-converting enzyme inhibitor perindopril treatment alters cardiovascular and subjective effects of methamphetamine in humans. Psychiatry Res 2010; 179: 96-100
  • 175 Visniauskas B, Perry JC, Oliveira V. et al. Cocaine administration increases angiotensin I-converting enzyme (ACE) expression and activity in the rat striatum and frontal cortex. Neurosci Lett 2012; 506: 84-88
  • 176 Zolezzi JM, Santos MJ, Bastías-Candia S et al. PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol Rev Camb Philos Soc 2017 [Epub ahead of print]
  • 177 Schupp M, Clemenz M, Gineste R. et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 2005; 54: 3442-3452
  • 178 Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta 2007; 1771: 1031-1045
  • 179 Culman J, Zhao Y, Gohlke P. et al. PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol Sci 2007; 28: 244-249
  • 180 Pilipović K, Župan Ž, Dolenec P. et al. A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 2015; 59: 8-20
  • 181 Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 2012; 32: 10117-10128
  • 182 Shindo T, Takasaki K, Uchida K. et al. Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer’s disease incorporating additional cerebrovascular disease factors. Biol Pharm Bull 2012; 35: 2141-2147
  • 183 Cheng H, Shang Y, Jiang L. et al. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer’s disease and mild-to-moderate Alzheimer's disease: a meta-analysis. Int J Neurosci 2016; 126: 299-307
  • 184 Barbiero JK, Santiago R, Tonin FS. et al. PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2014; 53: 35-44
  • 185 Dickey AS, Pineda VV, Tsunemi T. et al. PPARδ repression in Huntington’s disease and its essential role in CNS translate into a potent agonist therapy. Nature Medicine 2016; 22: 37-45
  • 186 Kariharan T, Nanayakkara G, Parameshwaran K. et al. Central activation of PPARgamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression. Neurobiol Aging 2015; 36: 1451-1461
  • 187 Min LJ, Mogi M, Shudou M. et al. Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice. Hypertension 2012; 59: 1079-1088
  • 188 Ouk T, Potey C, Gautier S. et al. PPARs: a potential target for a disease-modifying strategy in stroke. Curr Drug Targets 2013; 14: 752-767
  • 189 Villapol S, Balarezo MG, Affram K. et al. Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 2015; 138: 3299-3315
  • 190 Kemp DE, Ismail-Beigi F, Calabrese JR. Antidepressant response associated with pioglitazone: support for an overlapping pathophysiology between major depression and metabolic syndrome. Am J Psychiatry 2009; 166: 619
  • 191 Koponen H, Jokelainen J, Keinänen-Kiukaanniemi S. et al. Metabolic syndrome predisposes to depressive symptoms: a population-based 7-year follow-up study. J Clin Psychiatry 2008; 69: 178-182
  • 192 Colle R, de Larminat D, Rotenberg S. et al. Pioglitazone could induce remission in major depression: a meta-analysis. Neuropsychiatr Dis Treat 2016; 13: 9-16
  • 193 Colle R, de Larminat D, Rotenberg S. et al. PPAR-γ Agonists for the Treatment of Major Depression: A Review. Pharmacopsychiatry 2017; 50: 49-55
  • 194 Martínez-Gras I, Pérez-Nievas BG, García-Bueno B. et al. The anti-inflammatory prostaglandin 15d-PGJ2 and its nuclear receptor PPARgamma are decreased in schizophrenia. Schizophr Res 2011; 128: 15-22
  • 195 Yi Z, Fan X, Wang J. et al. Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: a pilot study. Psychiatry Res 2012; 200: 79-82
  • 196 Liu YR, Hu TM, Lan TH. et al. Association of the PPAR-γ gene with altered glucose levels and psychosis profile in schizophrenia patients exposed to antipsychotics. Psychiatry Investig 2014; 11: 179-185
  • 197 Brandl EJ, Tiwari AK, Zai CC. et al. No evidence for a role of the peroxisome proliferator-activated receptor gamma (PPARG) and adiponectin (ADIPOQ) genes in antipsychotic-induced weight gain. Psychiatry Res 2014; 219: 255-260
  • 198 Stopponi S, Somaini L, Cippitelli A. et al. Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry 2011; 69: 642-649
  • 199 Mascia P, Pistis M, Justinova Z. et al. Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry 2011; 69: 633-641
  • 200 Jackson A, Bagdas D, Muldoon PP. et al. In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence. Neuropharmacology 2017; 118: 38-45
  • 201 García-Bueno B, Madrigal JL, Lizasoain I. et al. Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats. Biol Psychiatry 2005; 57: 885-894
  • 202 McIntyre RS, Soczynska JK, Lewis GF. et al. Managing psychiatric disorders with antidiabetic agents: translational research and treatment opportunities. Expert Opin Pharmacother 2006; 7: 1305-1321
  • 203 Ryan KK, Grayson BE, Jones KR. et al. Physiological responses to acute psychological stress are reduced by the PPARγ agonist rosiglitazone. Endocrinology 2012; 153: 1279-1287