Advertisement

Translational Stroke Research

, Volume 6, Issue 2, pp 107–115 | Cite as

Long-term Effect of Telmisartan on Alzheimer’s Amyloid Genesis in SHR-SR After tMCAO

  • Tomoko Kurata
  • Violeta Lukic
  • Miki Kozuki
  • Daisuke Wada
  • Kazunori Miyazaki
  • Nobutoshi Morimoto
  • Yasuyuki Ohta
  • Kentaro Deguchi
  • Toru Yamashita
  • Nozomi Hishikawa
  • Kosuke Matsuzono
  • Yoshio Ikeda
  • Tatsushi Kamiya
  • Koji Abe
Original Article

Abstract

Telmisartan is expected to reduce not only the level of blood pressure but also neuroinflammation and neurotoxicity via pleiotrophic effects as a metabo-sartan. We examined the effects of telmisartan on Alzheimer’s disease (AD) pathology in spontaneously hypertensive rat stroke resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO) by giving either telmisartan at 0 (vehicle), 0.3 mg/kg/day (low dose, with no reduction of blood pressure), or 3 mg/kg/day (high dose, with a significant reduction of blood pressure) p.o. from 3 months (M) of age, and performed immunohistological analysis at 6, 12, and 18 M of age. The numbers of amyloid β (Aβ)-positive neurons in the cerebral cortex and hippocampus and senile plaque (SP) in the ipsilateral cerebral cortex progressively increased with age until 18 M in the SHR-SR after tMCAO. On the other hand, low-dose telmisartan significantly reduced the number of Aβ-positive neuron as well as SP at 6, 12, and 18 M. High-dose telmisartan showed further reductions of the above AD pathology. The present study suggests that telmisartan reduced both intracellular Aβ and extracellular SP accumulations after tMCAO in SHR-SR, with a further improvement by combined BP lowering. Such a strong effect of telmisartan could provide a preventative approach for AD in post-stroke patients with hypertension.

Keywords

Alzheimer’s disease Amyloid β, Metabolic syndrome Spontaneously hypertensive rat Telmisartan Transient middle cerebral artery occlusion 

Notes

Acknowledgments

This work was partly supported by a Grant-in-Aid for Scientific Research (B) 21390267 and the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Grants-in-Aid for Aoki M, Matsuoka Y, Mizusawa H, Nakano I, Nishizawa M, Sasaki H, from the Ministry of Health, Labour and Welfare of Japan.

Conflict of Interest

We have no conflict of interest for this work.

References

  1. 1.
    Hayden KM, Zandi PP, Lyketsos CG, Khachaturian AS, Bastian LA, Charoonruk G, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis Assoc Disord. 2006;20(2):93–100.CrossRefPubMedGoogle Scholar
  2. 2.
    Mogi M, Horiuchi M. Neurovascular coupling in cognitive impairment associated with diabetes mellitus. Circ J. 2011;75(5):1042–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Skoog I, Gustafson D. Update on hypertension and Alzheimer's disease. Neurol Res. 2006;28(6):605–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Alexander RW. Leukocyte and endothelial angiotensin II type 1 receptors and microvascular thrombotic and inflammatory responses to hypercholesterolemia. Arterioscler, Thromb, Vasc Biol. 2006;26(2):240–1.CrossRefGoogle Scholar
  5. 5.
    Carnevale D, Mascio G, D'Andrea I, Fardella V, Bell RD, Branchi I, et al. Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012;60(1):188–97.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Kurata T, Miyazaki K, Kozuki M, Panin VL, Morimoto N, Ohta Y, et al. Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Res. 2011;1371:161–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y, et al. Atorvastatin and pitavastatin reduce senile plaques and inflammatory responses in a mouse model of Alzheimer's disease. Neurol Res. 2012;34(6):601–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Sabbatini M, Catalani A, Consoli C, Marletta N, Tomassoni D, Avola R. The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mech Ageing Dev. 2002;123(5):547–59.CrossRefPubMedGoogle Scholar
  9. 9.
    Pravenec M, Landa V, Zidek V, Musilova A, Kazdova L, Qi N, et al. Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension. Physiol Res. 2003;52(6):681–8.PubMedGoogle Scholar
  10. 10.
    Sanz-Rosa D, Oubina MP, Cediel E, de Las HN, Vegazo O, Jimenez J, et al. Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system. Am J Physiol Heart Circ Physiol. 2005;288(1):H111–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Korenova M, Zilka N, Stozicka Z, Bugos O, Vanicky I, Novak M. NeuroScale, the battery of behavioral tests with novel scoring system for phenotyping of transgenic rat model of tauopathy. J Neurosci Methods. 2009;177(1):108–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, et al. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006;580(15):3582–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Zilka N, Stozicka Z, Kovac A, Pilipcinec E, Bugos O, Novak M. Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. J Neuroimmunol. 2009;209(1–2):16–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75 years and older: relationship of antihypertensive medication use. Arch Neurol. 1999;56(8):991–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Murray MD, Lane KA, Gao S, Evans RM, Unverzagt FW, Hall KS, et al. Preservation of cognitive function with antihypertensive medications: a longitudinal analysis of a community-based sample of African Americans. Arch Intern Med. 2002;162(18):2090–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Hajjar I, Brown L, Mack WJ, Chui H. Impact of angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series. Arch Neurol. 2012;1:7.Google Scholar
  18. 18.
    Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, et al. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007;117(11):3393–402.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Gohlke P, Weiss S, Jansen A, Wienen W, Stangier J, Rascher W, et al. AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats. J Pharmacol Exp Ther. 2001;298(1):62–70.PubMedGoogle Scholar
  20. 20.
    Maillard MP, Perregaux C, Centeno C, Stangier J, Wienen W, Brunner HR, et al. In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist. J Pharmacol Exp Ther. 2002;302(3):1089–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Araki K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertension. 2006;48(1):51–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 2004;43(5):993–1002.CrossRefPubMedGoogle Scholar
  23. 23.
    Sugimoto K, Qi NR, Kazdova L, Pravenec M, Ogihara T, Kurtz TW. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006;47(5):1003–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Rong X, Li Y, Ebihara K, Zhao M, Aini W, Kusakabe T, et al. An adipose tissue-independent insulin-sensitizing action of telmisartan: a study in lipodystrophic mice. J Pharmacol Exp Ther. 2009;331(3):1096–103.CrossRefPubMedGoogle Scholar
  25. 25.
    Abe K, Kawagoe J, Araki T, Aoki M, Kogure K. Differential expression of heat shock protein 70 gene between the cortex and caudate after transient focal cerebral ischaemia in rats. Neurol Res. 1992;14(5):381–5.PubMedGoogle Scholar
  26. 26.
    Wienen W, Schierok HJ. Effects of telmisartan, hydrochlorothiazide and their combination on blood pressure and renal excretory parameters in spontaneously hypertensive rats. J Renin Angiotensin Aldosterone Syst. 2001;2(2):123–8.PubMedGoogle Scholar
  27. 27.
    Kumai Y, Ooboshi H, Ago T, Ishikawa E, Takada J, Kamouchi M, et al. Protective effects of angiotensin II type 1 receptor blocker on cerebral circulation independent of blood pressure. Exp Neurol. 2008;210(2):441–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Rastas S, Verkkoniemi A, Polvikoski T, Juva K, Niinisto L, Mattila K, et al. Atrial fibrillation, stroke, and cognition: a longitudinal population-based study of people aged 85 and older. Stroke. 2007;38(5):1454–60.CrossRefPubMedGoogle Scholar
  29. 29.
    Reitz C, Bos MJ, Hofman A, Koudstaal PJ, Breteler MM. Prestroke cognitive performance, incident stroke, and risk of dementia: the Rotterdam Study. Stroke. 2008;39(1):36–41.CrossRefPubMedGoogle Scholar
  30. 30.
    Poon IO. Effects of antihypertensive drug treatment on the risk of dementia and cognitive impairment. Pharmacotherapy. 2008;28(3):366–75.CrossRefPubMedGoogle Scholar
  31. 31.
    Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC. Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med. 2001;125(4):489–92.PubMedGoogle Scholar
  32. 32.
    Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, et al. Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002;9(2):88–102.PubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    Saxby BK, Harrington F, Wesnes KA, McKeith IG, Ford GA. Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology. 2008;70(19 Pt 2):1858–66.PubMedGoogle Scholar
  35. 35.
    Tota S, Kamat PK, Awasthi H, Singh N, Raghubir R, Nath C, et al. Candesartan improves memory decline in mice: involvement of AT1 receptors in memory deficit induced by intracerebral streptozotocin. Behav Brain Res. 2009;199(2):235–40.CrossRefPubMedGoogle Scholar
  36. 36.
    Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Haraguchi T, Iwasaki K, Takasaki K, Uchida K, Naito T, Nogami A, et al. Telmisartan, a partial agonist of peroxisome proliferator-activated receptor gamma, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia. Brain Res. 2010;1353:125–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Haraguchi T, Iwasaki K, Takasaki K, Uchida K, Naito T, Nogami A, et al. Telmisartan, a partial agonist of peroxisome proliferator-activated receptor gamma, improves impairment of spatial memory and hippocampal apoptosis in rats treated with repeated cerebral ischemia. Brain Res. 2010;1353:125–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Derosa G, Ragonesi PD, Mugellini A, Ciccarelli L, Fogari R. Effects of telmisartan compared with eprosartan on blood pressure control, glucose metabolism and lipid profile in hypertensive, type 2 diabetic patients: a randomized, double-blind, placebo-controlled 12-month study. Hypertens Res. 2004;27(7):457–64.CrossRefPubMedGoogle Scholar
  40. 40.
    Aoki A, Ogawa T, Sumino H, Kumakura H, Takayama Y, Ichikawa S, et al. Long-term effects of telmisartan on blood pressure, the renin-angiotensin-aldosterone system, and lipids in hypertensive patients. Heart Vessels. 2012;25(3):195–202.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Tomoko Kurata
    • 1
  • Violeta Lukic
    • 1
  • Miki Kozuki
    • 1
  • Daisuke Wada
    • 1
  • Kazunori Miyazaki
    • 1
  • Nobutoshi Morimoto
    • 1
  • Yasuyuki Ohta
    • 1
  • Kentaro Deguchi
    • 1
  • Toru Yamashita
    • 1
  • Nozomi Hishikawa
    • 1
  • Kosuke Matsuzono
    • 1
  • Yoshio Ikeda
    • 1
  • Tatsushi Kamiya
    • 1
  • Koji Abe
    • 1
  1. 1.Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan

Personalised recommendations