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.
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References
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 5:9748
Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508
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 242:345–352
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
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 26:263–271
Chauhan V, Chauhan A (2006) Oxidative stress in Alzheimer’s disease. Pathophysiology 13(3):195–208
Choi EJ (2008) Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci 82(21–22):1059–1064
Cohen SJ, Stackman RW Jr (2015) Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav Brain Res 285:105–117
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):1685–1690
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):14385–14390
Ebert U, Kirch W (1998) Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Investig 28(11):944–949
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):273–285
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):137–147
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):4491–4500
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):131–138
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):3367–3374
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):846–851
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):2576–2582
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):5779–5785
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):1082–1090
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):825–835
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):455–463
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):235–245
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 87:65–74
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem. 193(1):265–75
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60
Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219
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):331–337
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)
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):e00764
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358
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):323–331
Pepeu G, Grazia Giovannini M (2017 Sep 1) The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Res 1670:173–184
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):3159–3165
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):29–33
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):619–625
Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221(2):555–563
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 5:1278–1286
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):937–949
Thapa A, Chi EY (2015) Biflavonoids as potential small molecule therapeutics for Alzheimer’s disease. Adv Exp Med Biol 863:55–77
Turnbull MT, Coulson EJ (2017) Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting TauHyperphosphorylation in genetically susceptible mice. J Alzheimers Dis 55(3):1141–1154
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):2255–2260
Winterbourn CC, Hawkins RE, Brian M, Carrell RW (1975)The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85(2):337–341
Winters BD, Saksida LM, Bussey TJ (2008) Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev 32:1055–1070
Zarebczan B, Pinchot SN, Kunnimalaiyaan M, Chen H (2011) Hesperetin, a potential therapy for carcinoid cancer. Am J Surg 201(3):329–332
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.
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Ishola, I.O., Jacinta, A.A. & Adeyemi, O.O. Cortico-hippocampal memory enhancing activity of hesperetin on scopolamine-induced amnesia in mice: role of antioxidant defense system, cholinergic neurotransmission and expression of BDNF. Metab Brain Dis 34, 979–989 (2019). https://doi.org/10.1007/s11011-019-00409-0
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DOI: https://doi.org/10.1007/s11011-019-00409-0