Neuroprotective effect of renin angiotensin system blockers on experimentally induced Alzheimer’s disease in rats

Wafaa A. Hewedy, Wessam F. El-Hadidy


Background: Alzheimer’s disease (AD) is a major world-wide health problem. Much evidence points to a link between hypertension and AD. However, the exact effects of different antihypertensive drugs on AD need to be more assessed. The aim was to evaluate and compare the possible effects of perindopril, and candesartan on cognitive impairment, oxidative stress markers, and brain concentrations of amyloid beta-peptide (Aβ-P) in a rat model of induced dementia.

Methods: Thirty-two adult male Wistar rats were distributed among 4 groups; (1) normal controls; (2) rats with dementia induced by intracerebroventricular administration of streptozotocin (ICV-STZ) and received no treatment; (3) ICV-STZ rats treated orally with perindopril for 3 weeks; and (4) ICV-STZ rats treated orally with candesartan for 3 weeks. The assessed parameters were spatial memory by Morris Water Maze test, brain tissue level of total antioxidant capacity (TAC), reduced glutathione (GSH), lipid peroxidation product (malondialdehyde [MDA]), and Aβ-P.

Results: Both perindopril and candesartan attenuated STZ-induced memory impairment, caused a significant increase in TAC and GSH levels, reduced MDA levels, whereas only candesartan significantly reduced Aβ-P levels.

Conclusions: This study reports that candesartan and perindopril can reverse the free radical induced damages and resultant memory defects, and may suggest candesartan as worthy drugs for prevention of Aβ-P deposition in this animal model of AD.


Streptozotocin, Amyloid beta-peptide, Hypertension, Perindopril, Candesartan, Oxidative stress

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Cummings JL. Alzheimer’s disease. N Engl J Med. 2004;351(1):56-67.

Welsh-Bohmer KA, Plassman BL, Hayden KM. Genetic and environmental contributions to cognitive decline in aging and Alzheimer’s disease. Annu Rev Gerontol Geriatr. 2010;30:81-114.

Love S. Contribution of cerebral amyloid angiopathy to Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75:1-4.

Luchsinger JA, Mayeux R. Cardiovascular risk factors and Alzheimer’s disease. Curr Atheroscler Rep. 2004;6:261-6.

Skoog I, Gustafson D. Hypertension, hypertension-clustering factors and Alzheimer’s disease. Neurol Res. 2003;25(6):675-80.

Kehoe PG, Wilcock GK. Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer’s disease? Lancet Neurol. 2007;6(4):373-8.

Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, et al. Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists. Regul Pept. 2005;128(3):227-38.

Du LL, Chai DM, Zhao LN, Li XH, Zhang FC, Zhang HB, et al. AMPK activation ameliorates Alzheimer’s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer’s disease model in rats. J Alzheimers Dis. 2015;43(3):775-84.

Institute of Laboratory Animal Resources, (ILAR). Guide for the Care and Use of Laboratory Animals. NIH Publication No. 85-23. (Revised 1996). Washington, D.C.: National Academy Press; 1996.

Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, et al. In vivo cross sectional characterization of cerebral alterations induced by intracerebro ventricular administraion of streptozotocin. PLoS One. 2012;7(9):e46196.

Dong YF, Kataoka K, Tokutomi Y, Nako H, Nakamura T, Toyama K, et al. Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer’s disease. FASEB J. 2011;25(9):2911-20.

Sánchez-Lemus E, Honda M, Saavedra JM. Angiotensin II 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(1):84-92.

Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, et al. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience. 2012;210:340-52.

Lin LW, Kuo YH, Hseu YC, Tsai CW, Hsieh MT, Chen SC, et al. Osthole improves spatial memory deficits in rats via hippocampal a 1-adrenergic and D 1/D 2 receptors. Evid Based Complement Alternat Med. 2013;2013:273682.

Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol. 2001;54(5):356-61.

Richardson RJ, Murphy SD. Effect of glutathione depletion on tissue deposition of methylmercury in rats. Toxicol Appl Pharmacol. 1975;31(3):505-19.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351-8.

Zhao Z, Ho L, Wang J, Qin W, Festa ED, Mobbs C, et al. Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer’s disease beta-amyloid neuropathology. FASEB J. 2005;19(14):2081-2.

Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, et al. Antihypertensive medication use and incident Alzheimer disease: the cache county study. Arch Neurol. 2006;63(5):686-92.

Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998;112(5):1199-208.

Ishrat T, Parveen K, Khan MM, Khuwaja G, Khan MB, Yousuf S, et al. Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Brain Res. 2009;1281:117-27.

Tota S, Kamat PK, Shukla R, Nath C. Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res. 2011;221(1):207-15.

Basso N, Paglia N, Stella I, de Cavanagh EM, Ferder L, del Rosario Lores Arnaiz M, et al. Protective effect of the inhibition of the renin-angiotensin system on aging. Regul Pept. 2005;128(3):247-52.

Tota S, Nath C, Najmi AK, Shukla R, Hanif K. Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism. Behav Brain Res. 2012;232(1):66-76.

Tota S, Hanif K, Kamat PK, Najmi AK, Nath C. Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function. Psychopharmacology (Berl). 2012;222(2):185-202.

Wright JW, Harding JW. The brain RAS and Alzheimer’s disease. Exp Neurol. 2010;223(2):326-33.

Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci. 2001;68(9):1021-9.

Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329-44.

Sultana R, Perluigi M, Butterfield DA. Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neurodegeneration from redox proteomics. Antioxid Redox Signal. 2006;8(11-12):2021-37.

Woltjer RL, Nghiem W, Maezawa I, Milatovic D, Vaisar T, Montine KS, et al. Role of glutathione in intracellular amyloid-alpha precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity. J Neurochem. 2005;93:1047-56.

Kim JS, Yun I, Choi YB, Lee KS, Kim YI. Ramipril protects from free radical induced white matter damage in chronic hypoperfusion in the rat. J Clin Neurosci 2008;15:174-8.

Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141-8.

Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002;10(3):279-88.

Quiroz-Baez R, Rojas E, Arias C. Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression. Neurochem Int. 2009;55(7):662-70.

Zhao Y, Zhao B. Natural antioxidants in prevention and management of Alzheimer’s disease. Front Biosci (Elite Ed). 2012;4:794-808.

Zhao W, Wang J, Ho L, Ono K, Teplow DB, Pasinetti GM. Identification of antihypertensive drugs which inhibit amyloid-beta protein oligomerization. J Alzheimers Dis. 2009;16(1):49-57.

Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001;276(51):47863-8.

Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280(45):37644-50.

Oba R, Igarashi A, Kamata M, Nagata K, Takano S, Nakagawa H. The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide. Eur J Neurosci. 2005;21(3):733-40.

Fournier A, Oprisiu-Fournier R, Serot JM, Godefroy O, Achard JM, Faure S, et al. Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors. Expert Rev Neurother. 2009;9(9):1413-31.