, Volume 223, Issue 3, pp 307–317 | Cite as

Defensive effect of natrium diethyldithiocarbamate trihydrate (NDDCT) and lisinopril in DOCA–salt hypertension-induced vascular dementia in rats

Original Investigation



Vascular dementia and hypertension are increasing day by day, with a high degree of co-occurrence. Tremendous amount of research work is required so that new pharmacological agents may be identified for their appropriate therapeutic utility to combat different dementing disorders.


This study investigates the effect of natrium diethyldithiocarbamate trihydrate (NDDCT), a nuclear factor kappa-B (NF-κB) inhibitor, as well as lisinopril, an angiotensin converting enzyme (ACE) inhibitor, on deoxycorticosterone acetate (DOCA) hypertension-induced vascular dementia in rats.


DOCA was used to induce hypertension and associated vascular dementia. Morris water maze (MWM) was used for testing learning and memory. Endothelial function was assessed by acetylcholine-induced endothelium-dependent relaxation of aortic strips. Different biochemical estimations were used to assess oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, and brain glutathione), nitric oxide levels (serum nitrite/nitrate), and cholinergic activity (brain acetyl cholinesterase activity).


DOCA treatment significantly raised the mean arterial blood pressure of rats, and these hypertensive rats performed poorly on MWM, reflecting impairment of learning and memory. DOCA treatment also impaired vascular endothelial function and different biochemical parameters. Treatments of NDDCT as well as lisinopril significantly attenuated DOCA hypertension-induced impairment of learning and memory, endothelial dysfunction, and changes in various biochemical levels.


DOCA–salt hypertension induces vascular dementia in rats. NF-κB as well as ACE inhibitors may be considered as potential pharmacological agents for the management of hypertension-induced vascular dementia.


Nuclear factor kappa-B Angiotensin converting enzyme Endothelial dysfunction Morris water maze Alzheimer’s disease Oxidative stress 



The authors are thankful to the Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala, Punjab, India for providing all the necessary facilities and funding to conduct this research. We are also thankful to Mr. A.S. Jaggi, Assistant Prof. in Pharmacology for his valuable suggestions.


  1. Anthony JD, Gary LP, Lisa AL, Douglas RS (2009) Role of NFκB in age-related vascular endothelial dysfunction in humans. Aging 1(8):678–680Google Scholar
  2. Barnes NM, Cheng CH, Costall B, Naylor RJ, Williams TJ, Wischik CM (1991) Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer’s disease. Eur J Pharmacol 200:289–292PubMedCrossRefGoogle Scholar
  3. Battistin L, Cagnin A (2010) Vascular cognitive disorder. A biological and clinical overview. Neurochem Res 3512:1933–1938CrossRefGoogle Scholar
  4. Beutler E, Duron O, Kelly B (1963) Reduced glutathione estimation. J Lb Clinical Med 61:82Google Scholar
  5. Bockman CS, Jeffries WB, Pettinger WA, Abel PW (1992) Reduced contractile sensitivity and vasopressin receptor affinity in DOCA–salt hypertension. Am J Physiol 262:1752–1758Google Scholar
  6. Borde P, Mohan M, Kasture S (2011) Effect of myricetin on deoxycorticosterone acetate DOCA–salt-hypertensive rats. Nat Prod Res 7:1–11Google Scholar
  7. Denis-Donini S, Dellarole A, Crociara P, Francese MT, Bortolotto V, Quadrato G, Canonico PL, Orsetti M, Ghi P, Memo M et al (2008) Impaired adult neurogenesis associated with short-term memory defects in NF-κB p50-deficient mice. J Neurosci 28:3911–3919PubMedCrossRefGoogle Scholar
  8. Ellman GL, Courtney DK, Andres V, Feathstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95PubMedCrossRefGoogle Scholar
  9. Fridmacher V, Kaltschmidt B, Goudeau B, Ndiaye D, Rossi FM, Pfeiffer J, Kaltschmidt C, Israel A, Memet S (2003) Forebrain-specific neuronal inhibition of nuclear factor-κB activity leads to loss of neuroprotection. J Neurosci 23:9403–9408PubMedGoogle Scholar
  10. Granic I, Dolga AM, Nijholt IM, Van Dijk G, Eisel UL (2009) Inflammation and NF-kappaB in Alzheimer’s disease and diabetes. J Alzheimers Dis 16(4):809–821PubMedGoogle Scholar
  11. Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR (2011) 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension 57(1):63–69PubMedCrossRefGoogle Scholar
  12. Jadhav A, Torlakovic E, Ndisang JF (2008) Interaction among heme oxygenase nuclear factor-kappaB and transcription activating factors in cardiac hypertrophy in hypertension. Hypertension 52(5):910–917PubMedCrossRefGoogle Scholar
  13. Jadhav A, Torlakovic E, Ndisang JF (2009) Hemin therapy attenuates kidney injury in deoxycorticosterone acetate–salt hypertensive rats. Am J Physiol Renal Physiol 296(3):F521–F534PubMedCrossRefGoogle Scholar
  14. Kalaria RN (2010) Vascular basis for brain degeneration faltering controls and risk factors for dementia. Nutr Rev 68(2):S74–S87PubMedCrossRefGoogle Scholar
  15. Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prullage M, Pfeiffer J, Lindecke A, Staiger V, Israel A et al (2006) NF-κB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 26:2936–2946PubMedCrossRefGoogle Scholar
  16. Kaltschmidt B, Kaltschmidt C (2009) NF-κB in the nervous system. Cold Spring Harb Perspect Biol 1:a001271PubMedCrossRefGoogle Scholar
  17. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038PubMedCrossRefGoogle Scholar
  18. Kandlikar SS, Fink GD (2011) Mild DOCA–salt hypertension sympathetic system and the role of renal nerves. Am J Physiol Heart Circ Physiol PMID: 21357502Google Scholar
  19. Khazaei M, Barmaki B, Nasimi A (2012) Protective role of selective nitric oxide synthase inhibitor for treatment of decompensated hemorrhagic shock in normotensive and hypertensive rats. Int J Prev Med 3(1):47–53PubMedGoogle Scholar
  20. Kim MK, Chung SW, Kim DH, Kim JM, Lee EK, Kim JY et al (2010) Modulation of age-related NF-kappaB activation by dietary zingerone via MAPK pathway. Exp Gerontol 45(6):419–426PubMedCrossRefGoogle Scholar
  21. Kim TI, Lee YK, Park SG, Choi IS, Ban JO, Park HK et al (2009) L-Theanine an amino acid in green tea attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med 47(11):1601–1610PubMedCrossRefGoogle Scholar
  22. Koladiya RU, Jaggi AS, Singh N, Sharma BK (2008) Ameliorative role of atorvastatin and pitavastatin in l-methionine induced vascular dementia in rats. BMC Pharmacol 8:14PubMedCrossRefGoogle Scholar
  23. Koladiya RU, Jaggi AS, Singh N, Sharma BK (2009) Beneficial effects of donepezil on vascular endothelial dysfunction-associated dementia induced by l-methionine in rats. J Health Sci 552:215–225CrossRefGoogle Scholar
  24. Kuhad A, Bishnoi M, Tiwari V, Chopra K (2009) Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 92(2):251–259PubMedCrossRefGoogle Scholar
  25. Levenson JM, Choi S, Lee SY, Cao YA, Ahn HJ, Worley KC, Pizzi M, Liou HC, Sweatt JD (2004) A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel. J Neurosci 24:3933–3943PubMedCrossRefGoogle Scholar
  26. Lorenza MM, Salvetti M, Belotti E, Paini A, Rosei CA, Aggiusti C, et al. (2011) Effects of barnidipine in comparison with hydrochlorothiazide on endothelial function as assessed by flow mediated vasodilatation in hypertensive patients. Blood Press PMID: 21332412Google Scholar
  27. Lowry OH, Rosebrough NJ, Far AL, Randall RJ (1951) Protein measurement with folin–phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  28. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-κB functions in synaptic signaling and behavior. Nat Neurosci 6:1072–1078PubMedCrossRefGoogle Scholar
  29. Miners JS, Ashby E, Van Helmond Z, Chalmers KA, Palmer LE, Love S et al (2008) Angiotensin-converting enzyme ACE levels and activity in Alzheimer’s disease and relationship of perivascular ACE-1 to cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 34:181–193PubMedCrossRefGoogle Scholar
  30. Miners S, Ashby E, Baig S, Harrison R, Tayler H, Speedy E 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 1:163–177PubMedGoogle Scholar
  31. Monsuez JJ, Gesquière-Dando A, Rivera S (2011) Cardiovascular prevention of cognitive decline. Cardiol Res Pract PMID: 21318115Google Scholar
  32. Moretti A, Gorini A, Villa RF (2011) Pharmacotherapy and prevention of vascular dementia. CNS Neurol Disord Drug Targets PMID: 21294702Google Scholar
  33. Morris RGM (1984) Developments of a water maze producer for studying spatial learning in the rats. J Neurosci Methods 11:47–60PubMedCrossRefGoogle Scholar
  34. Muhammad AB, Lokhandwala MF, Banday AA (2011) Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1 receptor dysfunction in obese rats. Am J Physiol Renal Physiol 300(1):F98–F104PubMedCrossRefGoogle Scholar
  35. Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiang M et al (2011) Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-1-9 axis in experimental hypertension. J Hypertens 29(4):706–715PubMedCrossRefGoogle Scholar
  36. Ohokawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefGoogle Scholar
  37. Ohrui T, Tomita N, Sato-Nakagawa T, Matsui T, Maruyama M, Niwa K et al (2004) Effects of centrally active ACE inhibitors on Alzheimer disease progression. Neurology 63:1324–1325PubMedCrossRefGoogle Scholar
  38. Parle M, Singh N (2004) Animal models for testing memory. Asia Pacific J Pharmacol 16:101–120Google Scholar
  39. Sahan-Firat S, Jennings BL, Yaghini FA, Song CY, Estes AM, Fang XR et al (2010) 23′45′-Tetramethoxystilbene prevents deoxycorticosterone–salt-induced hypertension contribution of cytochrome P-450 1B1. Am J Physiol Heart Circ Physiol 299(6):H1891–H1901PubMedCrossRefGoogle Scholar
  40. Sanz AB, Sanchez-Niño MD, Ramos AM, Moreno JA, Santamaría B, Ruiz-Ortega M et al (2010) NF-kappaB in renal inflammation. J Am Soc Nephrol 21(8):1254–1262PubMedCrossRefGoogle Scholar
  41. Sastry KV, Moudgal RP, Mohan J, Tyagi JS, Rao GS (2002) Spectrophotometric determination of serum nitrite and nitrate by copper–cadmium alloy. Anal Biochem 306(1):79–82PubMedCrossRefGoogle Scholar
  42. Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C et al (2001) Cortical alterations of angiotensin converting enzyme angiotensin II and AT1 receptor in Alzheimer’s dementia. Neurobiol Aging 22:541–546PubMedCrossRefGoogle Scholar
  43. Sharma B, Singh N (2011) Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats. Psychopharmacology PMID: 21225418Google Scholar
  44. Sharma B, Singh N (2010) Pitavastatin and 4′-hydroxy-3′-methoxyacetophenone HMAP reduce cognitive dysfunction in vascular dementia during experimental diabetes. Curr Neurovasc Res 7(3):180–191PubMedCrossRefGoogle Scholar
  45. Sharma B, Singh N, Singh M (2008a) Modulation of celecoxib- and streptozotocin-induced experimental dementia of Alzheimer’s disease by pitavastatin and donepezil. J Psychopharmacol 22(2):162–171PubMedCrossRefGoogle Scholar
  46. Sharma B, Singh N, Singh M, Jaggi AS (2008b) Exploitation of HIV protease inhibitor Indinavir as a memory restorative agent in experimental dementia. Pharmacol Biochem Behav 89(4):535–545PubMedCrossRefGoogle Scholar
  47. Silva PS, Fontana V, Palei AC, Sertório JT, Biagi C, Tanus-Santos JE (2011) Antihypertensive effects exerted by enalapril in mild to moderate hypertension are not associated with changes in the circulating levels of nitric oxide-related markers. Eur J Clin Pharmacol PMID: 21305271Google Scholar
  48. Sink KM, Leng X, Williamson J, Kritchevsky SB, Yaffe K, Kuller L et al (2009) Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension results from the cardiovascular health study. Arch Intern Med 169:1195–1202PubMedCrossRefGoogle Scholar
  49. Spiller SE, Logsdon NJ, Deckard LA, Sontheimer H (2011) Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo. BMC Cancer 11:136PubMedCrossRefGoogle Scholar
  50. Szasz T, Linder AE, Davis RP, Burnett R, Fink GD, Watts SW (2010) Allopurinol does not decrease blood pressure or prevent the development of hypertension in the DOCA–salt rat model. J Cardiovasc Pharmacol PMID: 20881613Google Scholar
  51. Szasz T, Watts SW (2010) Uric acid does not affect the acetylcholine-induced relaxation of aorta from normotensive and deoxycorticosterone acetate–salt hypertensive rats. J Pharmacol Exp Ther 333(3):758–763PubMedCrossRefGoogle Scholar
  52. Tota S, Kamat PK, Saxena G, Hanif K, Najmi AK, Nath C (2012) Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 226(1):317–330PubMedCrossRefGoogle Scholar
  53. Wang HD, Pagano PJ, Du Y (1998) Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide. Circ Res 82:810–818PubMedCrossRefGoogle Scholar
  54. Wehling M, Groth H (2011) Challenges of longevity in developed countries vascular prevention of dementia as an immediate clue to tackle an upcoming medical social and economic stretch. Neurodegener Dis PMID: 21228549Google Scholar
  55. Yamada K, Uchida S, Takahashi S, Takayama M, Nagata Y, Suzuki N et al (2010) Effect of a centrally active angiotensin-converting enzyme inhibitor perindopril on cognitive performance in a mouse model of Alzheimer’s disease. Brain Res 1352:176–186PubMedCrossRefGoogle Scholar
  56. Yang Q, Xue HM, Wong WT, Tian XY, Huang Y, Tsui SK et al (2011) AVE3085 an enhancer of endothelial nitric oxide synthase restores endothelial function and reduces blood pressure in spontaneously hypertensive rats. Br J Pharmacol. doi: 101111/j1476-5381201101308x
  57. Yasar S, Zhou J, Varadhan R, Carlson MC (2008) The use of angiotensin-converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women. Clin Pharmacol Ther 84:119–126PubMedCrossRefGoogle Scholar
  58. Zhang LN, Vincelette J, Chen D, Gless RD, Anandan SK, Rubanyi GM et al (2011) Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes obesity and hypertension. Eur J Pharmacol 654(1):68–74PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of MedicinePunjabi UniversityPatialaIndia

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