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Molecular Neurobiology

, Volume 55, Issue 2, pp 1725–1739 | Cite as

Angiotensin II Receptor Blockers Attenuate Lipopolysaccharide-Induced Memory Impairment by Modulation of NF-κB-Mediated BDNF/CREB Expression and Apoptosis in Spontaneously Hypertensive Rats

  • Ruby Goel
  • Shahnawaz Ali Bhat
  • Kashif Hanif
  • Chandishwar Nath
  • Rakesh ShuklaEmail author
Article

Abstract

Clinical studies demonstrated a positive correlation between hypertension and cognitive decline. Beneficial effects of angiotensin II receptor blockers on cognitive functions have also been reported earlier; however, its role in chronic neuroinflammation-induced memory impairment in the hypertensive state is not well understood. Therefore, in the present study, we investigated the effect of angiotensin II receptor blockers on memory impairment induced by lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHRs). Our data provides the strong evidence that intracerebroventricular (ICV) administration of LPS (25 μg) on the 1st, 4th, 7th, and 10th days leads to sustained neuroinflammation (as indicated by increased TNF-α, GFAP, COX-2, and NF-κB) and oxidative stress (increased reactive oxygen species (ROS) and nitrite levels) resulting in amyloid beta (Aβ1–42) deposition, apoptosis (increased Bax and decreased Bcl-2 expression as well as increased caspase-3 activity and TUNEL-positive cells), and memory impairment. Further, we found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation (as evident from the increased ACE expression, angiotensin II (Ang II) level, and angiotensin type 1 receptor (AT1R) expression) and decreased BDNF and p-CREB expression. Oral administration of candesartan (an AT1R blocker) at a non-anti-hypertensive dose (0.1 mg/kg) for 15 days attenuated LPS-induced (ICV) apoptosis, amyloidogenesis, and memory impairment. Candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling and by enhancing associated BDNF/CREB expression in SHRs. Our study also demonstrated that when both AT1R and angiotensin type 2 receptor (AT2R) were blocked by candesartan and PD123319 concomitantly, the protective effects of candesartan were blunted suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade.

Keywords

Lipopolysaccharide Hypertension Neuroinflammation Memory impairment AT1 receptor AT2 receptor 

Notes

Acknowledgements

This study was funded by the Indian Council of Medical Research (ICMR, project no. 58/13/2010BMS), New Delhi. Further, Senior Research Fellowships (SRFs) to RG from University Grants Commission (UGC) and SAB from ICMR, New Delhi, are greatly acknowledged. The CSIR-CDRI communication number of this manuscript is 9436.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2017_450_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1376 kb)

References

  1. 1.
    Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J et al (2001) Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56:1683–1689CrossRefPubMedGoogle Scholar
  2. 2.
    Obisesan TO (2009) Hypertension and cognitive function. Clin Geriatr Med 25:259–288CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Knecht S, Wersching H, Lohmann H, Berger K, Ringelstein EB (2009) How much does hypertension affect cognition?: explained variance in cross-sectional analysis of non-demented community-dwelling individuals in the SEARCH study. J Neurol Sci 283:149–152CrossRefPubMedGoogle Scholar
  4. 4.
    Shah NS, Vidal JS, Masaki K, Petrovitch H, Ross GW, Tilley C, DeMattos RB, Tracy RP et al (2012) Midlife blood pressure, plasma beta-amyloid, and the risk for Alzheimer disease: the Honolulu Asia aging study. Hypertension 59:780–786CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesbery W, Davis D, Nelson J, Hardman J et al (2005) AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol 57:98–103CrossRefPubMedGoogle Scholar
  6. 6.
    Goel R, Bhat SA, Rajasekar N, Hanif K, Nath C, Shukla R (2015) Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: protection by angiotensin converting enzyme inhibition. Pharmacol Biochem Behav 133:132–145CrossRefPubMedGoogle Scholar
  7. 7.
    Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, Okayama H, Mogi M et al (2009) Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension 53:356–362CrossRefPubMedGoogle Scholar
  8. 8.
    Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C, Muller-Spahn F (2001) Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia. Neurobiol Aging 22:541–546CrossRefPubMedGoogle Scholar
  9. 9.
    Miners S, Ashby E, Baig S, Harrison R, Tayler H, Speedy E, Prince JA, Love S et al (2009) Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res 1:163–177PubMedPubMedCentralGoogle Scholar
  10. 10.
    Srinivasan J, Jayadev S, Kumaran D, Ahamed KF, Suresh B, Ramanathan M (2005) Effect of losartan and enalapril on cognitive deficit caused by Goldblatt induced hypertension. Indian J Exp Biol 43:241–246PubMedGoogle Scholar
  11. 11.
    Tota S, Kamat PK, Awasthi H, Singh N, Raghubir R, Nath C, Hanif K (2009) Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin. Behav Brain Res 199:235–240CrossRefPubMedGoogle Scholar
  12. 12.
    Fogari R, Mugellini A, Zoppi A, Derosa G, Pasotti C, Fogari E, Preti P (2003) Influence of losartan and atenolol on memory function in very elderly hypertensive patients. J Hum Hypertens 17:781–785CrossRefPubMedGoogle Scholar
  13. 13.
    Hajjar I, Catoe H, Sixta S, Boland R, Johnson D, Hirth V, Wieland D, Eleazer P (2005) Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population. J Gerontol A Biol Sci Med Sci 60:67–73CrossRefPubMedGoogle Scholar
  14. 14.
    Guimond MO, Gallo-Payet N (2012) The angiotensin II type 2 receptor in brain functions: an update. Int J Hypertens 2012:351758CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gallo-Payet N, Guimond MO, Bilodeau L, Wallinder C, Alterman M, Hallberg A (2011) Angiotensin II, a neuropeptide at the frontier between endocrinology and neuroscience: is there a link between the angiotensin II type 2 receptor and Alzheimer’s disease? Front Endocrinol (Lausanne) 2:17Google Scholar
  16. 16.
    Chen da C, Wang J, Wang B, Yang SC, Zhang CX, Zheng YL, Li YL, Wang N et al (2009) Decreased levels of serum brain-derived neurotrophic factor in drug-naive first-episode schizophrenia: relationship to clinical phenotypes. Psychopharmacology 207:375–380CrossRefPubMedGoogle Scholar
  17. 17.
    Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, Rastegar K, Moosavi M (2010) Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 634:84–88CrossRefPubMedGoogle Scholar
  18. 18.
    Psotta L, Rockahr C, Gruss M, Kirches E, Braun K, Lessmann V, Bock J, Endres T (2015) Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model. Front Behav Neurosci 9:58CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Simmons DA, Rex CS, Palmer L, Pandyarajan V, Fedulov V, Gall CM, Lynch G (2009) Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington’s disease knockin mice. Proc Natl Acad Sci U S A 106:4906–4911CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chen DY, Bambah-Mukku D, Pollonini G, Alberini CM (2012) Glucocorticoid receptors recruit the CaMKIIalpha-BDNF-CREB pathways to mediate memory consolidation. Nat Neurosci 15:1707–1714CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kitamura Y, Taniguchi T, Shimohama S (1999) Apoptotic cell death in neurons and glial cells: implications for Alzheimer’s disease. Jpn J Pharmacol 79:1–5CrossRefPubMedGoogle Scholar
  22. 22.
    Jiang T, Gao L, Shi J, Lu J, Wang Y, Zhang Y (2013) Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats. Pharmacol Res 67:84–93CrossRefPubMedGoogle Scholar
  23. 23.
    Goel R, Bhat SA, Hanif K, Nath C, Shukla R (2016) Perindopril attenuates lipopolysaccharide-induced amyloidogenesis and memory impairment by suppression of oxidative stress and RAGE activation. ACS Chem Neurosci 7:206–217CrossRefPubMedGoogle Scholar
  24. 24.
    Tota S, Hanif K, Kamat PK, Najmi AK, Nath C (2012) Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function. Psychopharmacology 222:185–202CrossRefPubMedGoogle Scholar
  25. 25.
    Cuzzocrea S, Chatterjee PK, Mazzon E, Dugo L, Serraino I, Britti D, Mazzullo G, Caputi AP et al (2002) Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation. Br J Pharmacol 135:496–510CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H] norepinephrine, [3H] dopamine and [3H] dopa in various regions of the brain. J Neurochem 13:655–669CrossRefPubMedGoogle Scholar
  27. 27.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  28. 28.
    Bhat SA, Goel R, Shukla R, Hanif K (2015) Angiotensin receptor blockade modulates NFkappaB and STAT3 signaling and inhibits glial activation and neuroinflammation better than angiotensin-converting enzyme inhibition. Mol Neurobiol.Google Scholar
  29. 29.
    Harir N, Pecquet C, Kerenyi M, Sonneck K, Kovacic B, Nyga R, Brevet M, Dhennin I et al (2007) Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias. Blood 109:1678–1686CrossRefPubMedGoogle Scholar
  30. 30.
    Bhat, S. A.; Goel, R.; Shukla, R.; Hanif, K., Platelet CD40L induces activation of astrocytes and microglia in hypertension. Brain Behav Immun 2016.Google Scholar
  31. 31.
    Paxinos G, Watson CR, Emson PC (1980) AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 3(2):129–149CrossRefPubMedGoogle Scholar
  32. 32.
    Fogari R, Mugellini A, Zoppi A, Marasi G, Pasotti C, Poletti L, Rinaldi A, Preti P (2004) Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension. Eur J Clin Pharmacol 59:863–868CrossRefPubMedGoogle Scholar
  33. 33.
    Fournier A, Oprisiu-Fournier R, Serot JM, Godefroy O, Achard JM, Faure S, Mazouz H, Temmar M et al (2009) 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 9:1413–1431CrossRefPubMedGoogle Scholar
  34. 34.
    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:b5465Google Scholar
  35. 35.
    Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, Gleiter CH, Frey WH (2010) Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res 13:195–201CrossRefPubMedGoogle Scholar
  36. 36.
    Jing F, Mogi M, Sakata A, Iwanami J, Tsukuda K, Ohshima K, Min LJ, Steckelings UM et al (2012) Direct stimulation of angiotensin II type 2 receptor enhances spatial memory. J Cereb Blood Flow Metab 32:248–255CrossRefPubMedGoogle Scholar
  37. 37.
    Faure S, Bureau A, Oudart N, Javellaud J, Fournier A, Achard JM (2008) Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors. J Hypertens 26:2008–2015CrossRefPubMedGoogle Scholar
  38. 38.
    Carey RM, Jin XH, Siragy HM (2001) Role of the angiotensin AT2 receptor in blood pressure regulation and therapeutic implications. Am J Hypertens 14:98S–102SCrossRefPubMedGoogle Scholar
  39. 39.
    Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T (2014) AT(2) receptor and tissue injury: therapeutic implications. Curr Hypertens Rep 16:416CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    You D, Loufrani L, Baron C, Levy BI, Widdop RE, Henrion D (2005) High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation 111:1006–1011CrossRefPubMedGoogle Scholar
  41. 41.
    Shibata K, Makino I, Shibaguchi H, Niwa M, Katsuragi T, Furukawa T (1997) Up-regulation of angiotensin type 2 receptor mRNA by angiotensin II in rat cortical cells. Biochem Biophys Res Commun 239:633–637CrossRefPubMedGoogle Scholar
  42. 42.
    Zhang ZH, Yu Y, Wei SG, Felder RB (2010) Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P) H oxidase-dependent mitogen-activated protein kinase signaling. J Hypertens 28:806–816CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, Dole W, Rutledge JC (2002) Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. Physiol Genomics 11:21–30CrossRefPubMedGoogle Scholar
  44. 44.
    Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI et al (2007) Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther 322:1051–1058CrossRefPubMedGoogle Scholar
  45. 45.
    Taguchi I, Toyoda S, Takano K, Arikawa T, Kikuchi M, Ogawa M, Abe S, Node K et al (2013) Irbesartan, an angiotensin receptor blocker, exhibits metabolic, anti-inflammatory and antioxidative effects in patients with high-risk hypertension. Hypertens Res 36:608–613CrossRefPubMedGoogle Scholar
  46. 46.
    Sabuhi R, Ali Q, Asghar M, Al-Zamily NR, Hussain T (2011) Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats. Am J Physiol Renal Physiol 300:F700–F706CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Song B, Ao Q, Niu Y, Shen Q, Zuo H, Zhang X, Gong Y (2013) Amyloid beta-peptide worsens cognitive impairment following cerebral ischemia-reperfusion injury. Neural Regen Res 8:2449–2457PubMedPubMedCentralGoogle Scholar
  48. 48.
    Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D et al (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97:395–406CrossRefPubMedGoogle Scholar
  49. 49.
    Ivins KJ, Thornton PL, Rohn TT, Cotman CW (1999) Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8. Neurobiol Dis 6:440–449CrossRefPubMedGoogle Scholar
  50. 50.
    Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, Oezatalay D et al (2000) Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. J Cell Physiol 185:253–259CrossRefPubMedGoogle Scholar
  51. 51.
    Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM (1997) Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 81:970–976CrossRefPubMedGoogle Scholar
  52. 52.
    Kazanis I, Giannakopoulou M, Philippidis H, Stylianopoulou F (2004) Alterations in IGF-I, BDNF and NT-3 levels following experimental brain trauma and the effect of IGF-I administration. Exp Neurol 186:221–234CrossRefPubMedGoogle Scholar
  53. 53.
    Koda M, Murakami M, Ino H, Yoshinaga K, Ikeda O, Hashimoto M, Yamazaki M, Nakayama C et al (2002) Brain-derived neurotrophic factor suppresses delayed apoptosis of oligodendrocytes after spinal cord injury in rats. J Neurotrauma 19:777–785CrossRefPubMedGoogle Scholar
  54. 54.
    Arancibia S, Silhol M, Mouliere F, Meffre J, Hollinger I, Maurice T, Tapia-Arancibia L (2008) Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 31:316–326CrossRefPubMedGoogle Scholar
  55. 55.
    Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME (1997) CREB: a major mediator of neuronal neurotrophin responses. Neuron 19:1031–1047CrossRefPubMedGoogle Scholar
  56. 56.
    Cirulli F, Berry A, Chiarotti F, Alleva E (2004) Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus 14:802–807CrossRefPubMedGoogle Scholar
  57. 57.
    Alonso M, Vianna MR, Izquierdo I, Medina JH (2002) Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. Cell Mol Neurobiol 22:663–674CrossRefPubMedGoogle Scholar
  58. 58.
    Kitagawa K (2007) CREB and cAMP response element-mediated gene expression in the ischemic brain. FEBS J 274:3210–3217CrossRefPubMedGoogle Scholar
  59. 59.
    Tanaka K (2001) Alteration of second messengers during acute cerebral ischemia - adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein. Prog Neurobiol 65:173–207CrossRefPubMedGoogle Scholar
  60. 60.
    Ramirez SH, Sanchez JF, Dimitri CA, Gelbard HA, Dewhurst S, Maggirwar SB (2001) Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappaB (NF-kappaB)-dependent mechanism. J Neurochem 78:874–889CrossRefPubMedGoogle Scholar
  61. 61.
    Shenkar R, Yum HK, Arcaroli J, Kupfner J, Abraham E (2001) Interactions between CBP, NF-kappaB, and CREB in the lungs after hemorrhage and endotoxemia. Am J Physiol Lung Cell Mol Physiol 281:L418–L426CrossRefPubMedGoogle Scholar
  62. 62.
    Wen AY, Sakamoto KM, Miller LS (2010) The role of the transcription factor CREB in immune function. J Immunol 185:6413–6419CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C (1997) Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci U S A 94:2642–2647CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Umschweif G, Liraz-Zaltsman S, Shabashov D, Alexandrovich A, Trembovler V, Horowitz M, Shohami E (2014) Angiotensin receptor type 2 activation induces neuroprotection and neurogenesis after traumatic brain injury. Neurotherapeutics 11:665–678CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Ruby Goel
    • 1
  • Shahnawaz Ali Bhat
    • 1
  • Kashif Hanif
    • 1
  • Chandishwar Nath
    • 2
  • Rakesh Shukla
    • 1
    Email author
  1. 1.Division of PharmacologyCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Division of ToxicologyCSIR-Central Drug Research InstituteLucknowIndia

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