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Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function

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Abstract

Rational

Inhibition of renin–angiotensin system (RAS) improves cognitive functions in hypertensive patients. However, role of AT1 and AT2 receptors in memory impairment due to cholinergic hypofunction is unexplored.

Objective

This study investigated the role of AT1 and AT2 receptors in cerebral blood flow (CBF), cholinergic neurotransmission, and cerebral energy metabolism in scopolamine-induced amnesic mice.

Methods

Scopolamine was given to male Swiss albino mice to induce memory impairment tested in passive avoidance and Morris water maze tests after a weeklong administration of blocker of AT1 receptor, candesartan, and AT2 receptor, PD123, 319. CBF was measured by laser Doppler flowmetry. Biochemical and molecular studies were done in cortex and hippocampus of mice brain.

Results

Scopolamine caused memory impairment, reduced CBF, acetylcholine (ACh) level, elevated acetylcholinesterase (AChE) activity, and malondialdehyde (MDA). Administration of vehicle had no significant effect on any parameter in comparison to control. Candesartan prevented scopolamine-induced amnesia, restored CBF and ACh level, and decreased AChE activity and MDA level. In contrast, PD123, 319 was not effective. However, the effect of AT1 receptor blocker on memory, CBF, ACh level, and oxidative stress was blunted by concomitant blockade of AT2 receptor. Angiotensin-converting enzyme (ACE) activity, ATP level, and mRNA expression of AT1, AT2, and ACE remained unaltered.

Conclusion

The study suggests that activation of AT1 receptors appears to be involved in the scopolamine-induced amnesia and that AT2 receptors contribute to the beneficial effects of candesartan. Theses finding corroborated the number of clinical studies that RAS inhibition in hypertensive patients could be neuroprotective.

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References

  • Awasthi H, Tota S, Hanif K, Nath C, Shukla R (2010) Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow. Life Sci 86:87–94

    Article  PubMed  CAS  Google Scholar 

  • Baranov D, Armstead WM (2003) Selective blockade of AT1 receptor attenuates impairment of hypotensive autoregulation and improves cerebral blood flow after brain injury in the newborn pig. Anesthesiology 99:1118–24

    Article  PubMed  CAS  Google Scholar 

  • Barnes JM, Barnes NM, Costall B, Horovitz ZP, Naylor RJ (1989) Angiotensin II inhibits the release of [3H]acetylcholine from rat entorhinal cortex in vitro. Brain Res 491:136–43

    Article  PubMed  CAS  Google Scholar 

  • Barnes JM, Barnes NM, Costall B, Horovitz ZP, Ironside JW, Naylor RJ, Williams TJ (1990) Angiotensin II inhibits cortical cholinergic function: implications for cognition. J Cardiovasc Pharmacol 16:234–8

    Article  PubMed  CAS  Google Scholar 

  • Barnes NM, Costall B, Kelly ME, Murphy DA, Naylor RJ (1991) Cognitive enhancing actions of PD123177 detected in a mouse habituation paradigm. Neuroreport 2:351–3

    Article  PubMed  CAS  Google Scholar 

  • Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529

    Article  PubMed  CAS  Google Scholar 

  • Bassant MH, Jazat F, Lamour Y (1993) Tetrahydroaminoacridine and physostigmine increase cerebral glucose utilization in specific cortical and subcortical regions in the rat. J Cereb Blood Flow Metab 13:855–64

    Article  PubMed  CAS  Google Scholar 

  • 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–102S

    Article  PubMed  CAS  Google Scholar 

  • Colado MI, O'Shea E, Granados R, Misra A, Murray TK, Green AR (1997) A study of the neurotoxic effect of MDMA (‘ecstasy’) on 5-HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy. Br J Pharmacol 121:827–33

    Article  PubMed  CAS  Google Scholar 

  • Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM (2011) Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimers Dis 26:699–708

    PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–7

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  PubMed  CAS  Google Scholar 

  • Engelhorn T, Goerike S, Doerfler A, Okorn C, Forsting M, Heusch G, Schulz R (2004) The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats. J Cereb Blood Flow Metab 24:467–74

    Article  PubMed  Google Scholar 

  • Ertl G, Hu K (2001) Anti-ischemic potential of drugs related to the renin-angiotensin system. J Cardiovasc Pharmacol 37(Suppl 1):S11–20

    Article  PubMed  CAS  Google Scholar 

  • Estrup TM, Paulson OB, Strandgaard S (2001) No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation. J Renin Angiotensin Aldosterone Syst 2:188–92

    Article  PubMed  CAS  Google Scholar 

  • 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 26:2008–15

    Article  PubMed  CAS  Google Scholar 

  • Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF (2011) Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets 11:1193–206

    Google Scholar 

  • 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 17:781–5

    Article  PubMed  CAS  Google Scholar 

  • Fukuda K, Hirooka K, Mizote M, Nakamura T, Itano T, Shiraga F (2011) Neuroprotection against retinal ischemia–reperfusion injury by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci 51:3629–38

    Article  Google Scholar 

  • Gard PR (2002) The role of angiotensin II in cognition and behaviour. Eur J Pharmacol 438:1–14

    Article  PubMed  CAS  Google Scholar 

  • Giacobini E (1990) The cholinergic system in Alzheimer disease. Prog Brain Res 84:321–32

    Article  PubMed  CAS  Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15 N]nitrate in biological fluids. Anal Biochem 126:131–8

    Article  PubMed  CAS  Google Scholar 

  • Hanif K, Snehlata PMC, Arif E, Biswas P, Fahim M, Pasha MA, Pasha S (2009) Effect of 3-thienylalanine-ornithine-proline, new sulfur-containing angiotensin-converting enzyme inhibitor on blood pressure and oxidative stress in spontaneously hypertensive rats. J Cardiovasc Pharmacol 53:145–50

    Article  PubMed  CAS  Google Scholar 

  • Hasselmo ME (2006) The role of acetylcholine in learning and memory. Curr Opin Neurobiol 16:710–5

    Article  PubMed  CAS  Google Scholar 

  • Hoglund AU, Hamilton C, Lindblom L (2000) Effects of microdialyzed oxotremorine, carbachol, epibatidine, and scopolamine on intraspinal release of acetylcholine in the rat. J Pharmacol Exp Ther 295:100–4

    PubMed  CAS  Google Scholar 

  • Honer WG, Prohovnik I, Smith G, Lucas LR (1988) Scopolamine reduces frontal cortex perfusion. J Cereb Blood Flow Metab 8:635–41

    Article  PubMed  CAS  Google Scholar 

  • Inaba S, Iwai M, Furuno M, Tomono Y, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M (2009) Continuous activation of renin–angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension 53:356–62

    Article  PubMed  CAS  Google Scholar 

  • Jeong EJ, Lee KY, Kim SH, Sung SH, Kim YC (2008) Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana in scopolamine-treated mice. Eur J Pharmacol 588:78–84

    Article  PubMed  CAS  Google Scholar 

  • Jones RW, Wesnes KA, Kirby J (1991) Effects of NMDA modulation in scopolamine dementia. Ann N Y Acad Sci 640:241–4

    PubMed  CAS  Google Scholar 

  • Kapogiannis D, Mattson MP (2011) Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol 10:187–98

    Article  PubMed  CAS  Google Scholar 

  • Kehoe PG (2003) The renin–angiotensin–aldosterone system and Alzheimer s disease? J Renin Angiotensin Aldosterone Syst 4:80–93

    Article  PubMed  CAS  Google Scholar 

  • Kehoe PG, Miners S, Love S (2009) Angiotensins in Alzheimer's disease—friend or foe? Trends Neurosci 32:619–28

    Article  PubMed  CAS  Google Scholar 

  • Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B (2011) Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 340:b5465

    Article  Google Scholar 

  • Liu JJ, Li DL, Zhou J, Sun L, Zhao M, Kong SS, Wang YH, Yu XJ, Zhou J, Zang WJ (2011) Acetylcholine prevents angiotensin II-induced oxidative stress and apoptosis in H9c2 cells. Apoptosis 16:94–103

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–75

    PubMed  CAS  Google Scholar 

  • Lu Q, Zhu YZ, Wong PT (2005) Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport 16:1963–7

    Article  PubMed  CAS  Google Scholar 

  • Maul B, von Bohlen und Halbach O, Becker A, Sterner-Kock A, Voigt JP, Siems WE, Grecksch G, Walther T (2008) Impaired spatial memory and altered dendritic spine morphology in angiotensin II type 2 receptor-deficient mice. J Mol Med 86:563–71

    Article  PubMed  CAS  Google Scholar 

  • Molchan SE, Matochik JA, Zametkin AJ, Szymanski HV, Cantillon M, Cohen RM, Sunderland T (1994) A double FDG/PET study of the effects of scopolamine in older adults. Neuropsychopharmacology 10:191–8

    PubMed  CAS  Google Scholar 

  • Mosimann R, Imboden H, Felix D (1996) The neuronal role of angiotensin II in thirst, sodium appetite, cognition and memory. Biol Rev Camb Philos Soc 71:545–59

    Article  PubMed  CAS  Google Scholar 

  • Nakano S, Asada T, Matsuda H, Uno M, Takasaki M (2001) Donepezil hydrochloride preserves regional cerebral blood flow in patients with Alzheimer’s disease. J Nucl Med 42:1441–5

    PubMed  CAS  Google Scholar 

  • Nishimura Y, Ito T, Saavedra JM (2000) Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 31:2478–86

    Article  PubMed  CAS  Google Scholar 

  • Nordberg A, Lilja A, Lundqvist H, Hartvig P, Amberla K, Viitanen M, Warpman U, Johansson M, Hellstrom-Lindahl E, Bjurling P et al (1992) Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography. Neurobiol Aging 13:747–58

    Article  PubMed  CAS  Google Scholar 

  • Ogawa M, Magata Y, Ouchi Y, Fukuyama H, Yamauchi H, Kimura J, Yonekura Y, Konishi J (1994) Scopolamine abolishes cerebral blood flow response to somatosensory stimulation in anesthetized cats: PET study. Brain Res 650:249–52

    Article  PubMed  CAS  Google Scholar 

  • Plaschke K, Hoyer S (1993) Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. Int J Dev Neurosci 11:477–83

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Chopra K, Kulkarni SK (1998) Involvement of cholinergic system in losartan-induced facilitation of spatial and short-term working memory. Neuropeptides 32:417–21

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Chopra K, Kulkarni SK (2001) Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm. Neuropeptides 35:65–9

    Article  PubMed  CAS  Google Scholar 

  • Saito K, Honda S, Egawa M, Tobe A (1985) Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine release from cortical and hippocampal slices of rats. Jpn J Pharmacol 39:410–4

    Article  PubMed  CAS  Google Scholar 

  • Sakurai T, Kato T, Mori K, Takano E, Watabe S, Nabeshima T (1998) Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study. Neurosci Lett 246:69–72

    Article  PubMed  CAS  Google Scholar 

  • Savaskan E (2005) The role of the brain renin-angiotensin system in neurodegenerative disorders. Curr Alzheimer Res 2:29–35

    Article  PubMed  CAS  Google Scholar 

  • 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 22:541–6

    Article  PubMed  CAS  Google Scholar 

  • Saxby BK, Harrington F, Wesnes KA, McKeith IG, Ford GA (2008) Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology 70:1858–66

    Article  PubMed  CAS  Google Scholar 

  • Saxena G, Singh SP, Pal R, Singh S, Pratap R, Nath C (2007) Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice. Pharmacol Biochem Behav 86:797–805

    Article  PubMed  CAS  Google Scholar 

  • Sharma D, Puri M, Tiwary AK, Singh N, Jaggi AS (2011) Antiamnesic effect of stevioside in scopolamine-treated rats. Indian J Pharmacol 42:164–7

    Google Scholar 

  • Shepherd J, Bill DJ, Dourish CT, Grewal SS, McLenachan A, Stanhope KJ (1996) Effects of the selective angiotensin II receptor antagonists losartan and PD123177 in animal models of anxiety and memory. Psychopharmacology (Berl) 126:206–18

    Article  CAS  Google Scholar 

  • Spignoli G, Pepeu G (1987) Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine. Pharmacol Biochem Behav 27:491–5

    Article  PubMed  CAS  Google Scholar 

  • 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 199:235–40

    Article  PubMed  CAS  Google Scholar 

  • Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–9

    Article  PubMed  CAS  Google Scholar 

  • Tota S, Kamat PK, Shukla R, Nath C (2011) Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res 221:207–215

    Article  PubMed  CAS  Google Scholar 

  • 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 226:317–30

    Article  PubMed  CAS  Google Scholar 

  • Tsukada H, Kakiuchi T, Ando I, Ouchi Y (1997) Functional activation of cerebral blood flow abolished by scopolamine is reversed by cognitive enhancers associated with cholinesterase inhibition: a positron emission tomography study in anaesthetized monkeys. J Pharmacol Exp Ther 281:1408–14

    PubMed  CAS  Google Scholar 

  • Wang C, Smith RL (1975) Lowry determination of protein in the presence of Triton X-100. Anal Biochem 63:414–7

    Article  PubMed  CAS  Google Scholar 

  • Wright JW, Harding JW (2011) The brain RAS and Alzheimer’s disease. Exp Neurol 223:326–33

    Article  Google Scholar 

  • Wyper D, Teasdale E, Patterson J, Montaldi D, Brown D, Hunter R, Graham D, McCulloch J (1993) Abnormalities in rCBF and computed tomography in patients with Alzheimer’s disease and in controls. Br J Radiol 66:23–7

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Financial support to Santoshkumar Tota from Council of Scientific and Industrial Research (CSIR) New Delhi, India is gratefully acknowledged.

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Authors and Affiliations

  1. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India

    Santoshkumar Tota, Kashif Hanif & Pradeep Kumar Kamat

  2. Division of Toxicology, CSIR-Central Drug Research Institute, Chattar Manzil Palace, Lucknow, Uttar Pradesh, India

    Chandishwar Nath

  3. Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India

    Abul Kalam Najmi

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  1. Santoshkumar Tota
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  2. Kashif Hanif
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Correspondence to Chandishwar Nath.

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CDRI communication number: 8191

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Tota, S., Hanif, K., Kamat, P.K. et al. Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function. Psychopharmacology 222, 185–202 (2012). https://doi.org/10.1007/s00213-012-2639-7

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  • DOI: https://doi.org/10.1007/s00213-012-2639-7

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