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Cortico-hippocampal memory enhancing activity of hesperetin on scopolamine-induced amnesia in mice: role of antioxidant defense system, cholinergic neurotransmission and expression of BDNF

  • Ismail O. IsholaEmail author
  • Abosi A. Jacinta
  • Olufunmilayo O. Adeyemi
Original Article
  • 59 Downloads

Abstract

Alzheimer disease (AD) is an age related neurodegenerative disease causing severe cognitive and memory decline in elderly people. Flavonoids play neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) or tau peptide into oligomers and fibrils. This study sought to investigate the effect of hesperetin (HPT) on scopolamine-induced memory impairments in mice. Mice were orally pretreated with HPT (1, 5 or 50 mg/kg) or vehicle (normal saline; 10 ml/kg) for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was administered 5 min before locomotor activity (open field test) and memory function (novel object recognition test (NORT) for 2 consecutive days and Morris water maze task (MWM) for 5 consecutive days). Levels of oxidative stress markers / brain derived neurotrophic factors (BDNF) and acetylcholinesterase activity were determined in the hippocampus and prefrontal cortex after completion of MWM task. Scopolamine caused no significant change in mice exploration of the familiar or novel object in the test session whereas the HPT-treated mice spent more time exploring the novel object more than familiar object in NORT. Scopolamine also increased the escape latency in acquisition phase and decreases time spent in target quadrant in probe phase which were ameliorated by the pretreatment with HPT. Scopolamine-induced alteration of oxidant-antioxidant balance, acetylcholinesterase activity and neurogenesis in the hippocampus and prefrontal cortex were attenuated by HPT treatment. This study showed that HPT ameliorated non-spatial/spatial learning and memory impairment by scopolamine possibly through enhancement of antioxidant defense, cholinergic and BDNF signaling.

Keywords

Brain derived neurotrophic factors Cholinergic neurotransmission Novel object recognition test Oxidative stress Neurogenesis Morris water maze task 

Notes

Acknowledgements

Authors are grateful to Mr. M. Chijioke of the Department of Pharmacology, Therapeutics and Toxicology and Mr. S.A. Adenekan of the Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, for their technical assistance.

Compliance with ethical standards

Conflict of interest

We do not have any conflict of interest to declare.

References

  1. Bajo R, Pusil S, López ME, Canuet L, Pereda E, Osipova D, Maestú F, Pekkonen E (2015) Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer’s disease. Sci Rep 5:9748CrossRefGoogle Scholar
  2. Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508CrossRefGoogle Scholar
  3. Bodduluru LN, Kasala ER, Barua CC, Karnam KC, Dahiya V, Ellutla M (2015) Antiproliferative and antioxidant potential of hesperetin against benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Chem Biol Interact 242:345–352CrossRefGoogle Scholar
  4. Bromley-Brits K, Deng Y, Song W (2011) Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp (53).  https://doi.org/10.3791/2920
  5. Brown RE, Corey SC, Moore AK (1999) Differences in measures of exploration and fear in MHC-congenic C57BL/6J and B6-H-2K mice. Behavioural Genetics 26:263–271Google Scholar
  6. Chauhan V, Chauhan A (2006) Oxidative stress in Alzheimer’s disease. Pathophysiology 13(3):195–208CrossRefGoogle Scholar
  7. Choi EJ (2008) Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci 82(21–22):1059–1064CrossRefGoogle Scholar
  8. Cohen SJ, Stackman RW Jr (2015) Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav Brain Res 285:105–117CrossRefGoogle Scholar
  9. Cohen SJ, Munchow AH, Rios LM, Zhang G, Asgeirsdóttir HN, Stackman RW Jr (2013) The rodent hippocampus is essential for nonspatial object memory. Curr Biol 23(17):1685–1690CrossRefGoogle Scholar
  10. Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN (2003) Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100(24):14385–14390CrossRefGoogle Scholar
  11. Ebert U, Kirch W (1998) Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Investig 28(11):944–949CrossRefGoogle Scholar
  12. Epp JR, Spritzer MD, Galea LA (2007) Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience. 149(2):273–285CrossRefGoogle Scholar
  13. Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66(2):137–147CrossRefGoogle Scholar
  14. Gómez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16(14):4491–4500CrossRefGoogle Scholar
  15. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Analytical Biochemistry 126(1):131–138Google Scholar
  16. Hirata A, Murakami Y, Shoji M, Kadoma Y, Fujisawa S (2005 Sep-Oct) Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activityon COX-2 expression. Anticancer Res 25(5):3367–3374Google Scholar
  17. Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57(6):846–851CrossRefGoogle Scholar
  18. Hwang SL, Yen GC (2009) Modulation of Akt, JNK, and p38 activation is involved in citrus flavonoid-mediated cytoprotection of PC12 cells challenged by hydrogen peroxide. J Agric Food Chem 57(6):2576–2582CrossRefGoogle Scholar
  19. Hwang SL, Yen GC (2011) Effect of hesperetin against oxidative stress via ER- and TrkA-mediated actions in PC12 cells. J Agric Food Chem 59(10):5779–5785Google Scholar
  20. Hwang SL, Lin JA, Shih PH, Yeh CT, Yen GC (2012) Pro-cellular survival and neuroprotection of citrus flavonoid: the actions of hesperetin in PC12 cells. Food Funct 3(10):1082–1090CrossRefGoogle Scholar
  21. Ishola IO, Tota S, Adeyemi OO, Agbaje EO, Narender T, Shukla R (2013) Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice: a behavioral and biochemical study. Pharm Biol 51(7):825–835CrossRefGoogle Scholar
  22. Ishola IO, Awoyemi AA, Afolayan GO (2016) Involvement of antioxidant system in the amelioration of scopolamine-induced memory impairment by grains of paradise (Aframomum melegueta K. Schum.) extract. Drug Res (Stuttg) 66(9):455–463CrossRefGoogle Scholar
  23. Ishola IO, Adamson FM, Adeyemi OO (2017) Ameliorative effect of kolaviron, a biflavonoid complex from Garcinia kola seeds against scopolamine-induced memory impairment in rats: role of antioxidant defense system. Metab Brain Dis 32(1):235–245CrossRefGoogle Scholar
  24. Kumar B, Gupta SK, Srinivasan BP, Nag TC, Srivastava S, Saxena R, Jha KA (2013) Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 87:65–74CrossRefGoogle Scholar
  25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem. 193(1):265–75Google Scholar
  26. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60Google Scholar
  27. Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219CrossRefGoogle Scholar
  28. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3):331–337CrossRefGoogle Scholar
  29. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 8th edition (2011) Washington (DC): National Academies Press (US)Google Scholar
  30. Ning H, Cao D, Wang H, Kang B, Xie S, Meng Y (2017) Effects of haloperidol, olanzapine, ziprasidone, and PHA-543613 on spatial learning and memory in the Morris water maze test in naïve and MK-801-treated mice. Brain Behav 7(8):e00764CrossRefGoogle Scholar
  31. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358Google Scholar
  32. Parhiz H, Roohbakhsh A, Soltani F, Rezaee R, Iranshahi M (2015) Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res 29(3):323–331CrossRefGoogle Scholar
  33. Pepeu G, Grazia Giovannini M (2017 Sep 1) The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Res 1670:173–184CrossRefGoogle Scholar
  34. Rahman I, Kode A, Biswas SK (2006) Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 1(6):3159–3165Google Scholar
  35. Rainey-Smith S, Schroetke LW, Bahia P, Fahmi A, Skilton R, Spencer JP, Rice-Evans C, Rattray M, Williams RJ (2008) Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neurosci Lett 438(1):29–33CrossRefGoogle Scholar
  36. Ramos Reis PM, Eckhardt H, Denise P, Bodem F, Lochmann M (2013) Localization of scopolamine induced electrocortical brain activity changes, in healthy humans at rest. J Clin Pharmacol 53(6):619–625CrossRefGoogle Scholar
  37. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221(2):555–563CrossRefGoogle Scholar
  38. Seward ME, Swanson E, Norambuena A, Reimann A, Cochran JN, Li R, Roberson ED, Bloom GS (2013) Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer’s disease. J Cell Sci 126(Pt 5:1278–1286CrossRefGoogle Scholar
  39. Suganthy N, Malar DS, Devi KP (2016) Rhizophora mucronata attenuates beta-amyloid induced cognitive dysfunction, oxidative stress and cholinergic deficit in Alzheimer’s disease animal model. Metab Brain Dis 31(4):937–949CrossRefGoogle Scholar
  40. Thapa A, Chi EY (2015) Biflavonoids as potential small molecule therapeutics for Alzheimer’s disease. Adv Exp Med Biol 863:55–77CrossRefGoogle Scholar
  41. Turnbull MT, Coulson EJ (2017) Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting TauHyperphosphorylation in genetically susceptible mice. J Alzheimers Dis 55(3):1141–1154CrossRefGoogle Scholar
  42. Wang B, Li L, Jin P, Li M, Li J (2017) Hesperetin protects against inflammatory response and cardiac fibrosis in postmyocardial infarction mice by inhibiting nuclear factor κB signaling pathway. Exp Ther Med 14(3):2255–2260CrossRefGoogle Scholar
  43. Winterbourn CC, Hawkins RE, Brian M, Carrell RW (1975)The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85(2):337–341Google Scholar
  44. Winters BD, Saksida LM, Bussey TJ (2008) Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev 32:1055–1070CrossRefGoogle Scholar
  45. Zarebczan B, Pinchot SN, Kunnimalaiyaan M, Chen H (2011) Hesperetin, a potential therapy for carcinoid cancer. Am J Surg 201(3):329–332CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of MedicineUniversity of LagosLagosNigeria

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