Abstract
Morin hydrate (MH) is the major flavonoid constituent of Morus alba acclaimed to have antioxidant, anti-inflammatory, anti-stress and neuroprotective properties. However, report on the effect of MH on memory performance and the underlying mechanism following chronic stress exposure is lacking. The current study aimed at investigating the neuroprotective effect of MH on chronic unpredictable stress (CUS)-induced memory impairment in mice using the Y maze test. Mice were subjected to unpredicted stress for 14 days, during which MH (5, 10 and 20 mg/kg i.p) or 25 mg/kg Ginseng was administered to them. On the 14th day, 1 h after treatment, learning and memory deficit was evaluated using the Y maze test and thereafter brains were harvested for the estimation of glutathione (GSH), lipid peroxidation product; malondialdehyde (MDA) and nitrite. Levels of inflammatory mediators tumor necrosis factor-alpha (TNF-α) and interleukin1-beta (IL-1β), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-кB) expressions were also determined. The hippocampus was stained with hematoxylin-eosin (H&E) to examine any morphological changes in the neurons. Mice exposed to CUS showed evidence of impaired memory and increase levels of MDA, nitrite, TNF-α and IL-1β. Furthermore, CUS reduced GSH level, increased the expressions of iNOS and NFкB immune-positive cells and produced loss of neuronal cells in the hippocampus. The MH treatment however improved memory, reduced MDA and nitrite levels, and enhanced brain GSH levels in CUS-mice. Besides, MH reduced brain levels of TNF-α and IL-1β levels, down regulated the expressions of iNOS and NF-кB and rescue neurons in the hippocampal CA3 region of mice exposed to CUS. The results of the study indicate that MH improved CUS-induced memory impairment, which may be related to its ability to boost antioxidant defense system and suppress neuroinflammatory pathways.
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25 April 2022
A Correction to this paper has been published: https://doi.org/10.1007/s11011-022-00989-4
References
Adebesin A, Ajayi AM, Olonode EO, Omorogbe O, Umukoro S (2017) Methyl Jasmonate Ameliorates Unpredictable Chronic Mild Stress-Induced Behavioral and Biochemical Alterations in Mouse Brain. DDR 78:381–389
Banjarnahor SD, Artanti N (2014) Antioxidant properties of flavonoids. Med J Indonesia 23:239–244
Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Owoeye O, Olonode ET, Iwalewa EO (2018a) Probable mechanisms involved in the antipsychotic-like activity of morin in mice. Biomed Pharmacother 105:1079–1090
Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Umukoro S, Iwalewa EO (2018b) Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine-induced schizophrenia-like behavior by morin in mice. Brain Res Bull 139:292–306
Ben-Azu B, Aderibigbe AO, Eneni AO, Ajayi AM, Umukoro S, Iwalewa EO (2018c) Morin attenuates neurochemical changes and increased oxidative/nitrergic stress in brains of mice exposed to ketamine: prevention and reversal of schizophrenia-like symptoms. Neurochem Res 43:1745–1755
Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Omogbiya IA, Owoeye O, Umukoro S, Iwalewa EO (2019) Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia. Int Immunopharmacol 70:338–35
Bhatia N, Jaggi SA, Singh N, Anand P, Dhawan R (2011) Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis. J Nat Med 65:532–543
Bisaz R, Schachner M, Sandi C (2011) Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments. Hippocampus 21:56–71
Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol neurobiol 50:534–544
Butterfield DA, Drake J, Pocernich C, Castegna A (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7:548–554
Campos-Esparza MR, Sanchez-Gomez MV, Matut C (20090 Molecular mechanisms of neuroprotection by two natural antioxidant polyphenols. Cell Calcium 45:358–368
Casadesus G, Milliken EL, Webber KM, Bowen RL, Lei Z, Rao CV, Perry G, Keri RA, Smith MA (2007) Increases in luteinizing hormone are associated with declines in cognitive performance. Mol Cell Endocrinol 269:107–111
Cheng J, Dong S, Yi L, Geng D, Liu Q (2018) Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice. Int immunopharmacol 59:61–67
Christoffel DJ, Golden SA, Russo SJ (2011) Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 22:535–549
Conrad CD (2010) A critical review of chronic stress effects on spatial learning and memory. Prog Neuro-Psychopharmacol Biol Psychiatry 34:742–755
Conrad CD, McLaughlin KJ, Harman JS, Foltz C, Wieczorek L, Lightner E, Wright RL (2007) Chronic glucocorticoids increase hippocampal vulnerability to neurotoxicity under conditions that produce CA3 dendritic retraction but fail to impair spatial recognition memory. J Neurosci 27:8278–8285
Dá Mesquita S, Ferreira AC, Sousa JC, Correia-Neves M, Sousa N, Marques F (2016) Insights on the pathophysiology of Alzheimer's disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci biobehav R 68:547–562
Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL (2009) Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine—a PDE1 inhibitor. Euro J Pharm 620:49–56
Eltony SA, Elgayar SA (2014) Histological study on effect of Nigella sativa on aged olfactory system of female albino rat. Rom J Morpho Embryo 55:325–334
Fischer R, Maier O (2015) Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev
Going JJ (1994) Efficiently estimated histologic cell counts. Hum Pathol 25:333–336
Gornall AG, Bardawill CJ, David MM (1949) Determination of Serum proteins by means of the Biuret Reaction. J Biol Chem 177:751–766
Gottlieb M, Leal-Campanario R, Campos-Esparza M, Sanchez-Gomez M, Alberdi E, Arranz A, Delgado-Garcıa J, Gruart A, Matute C (2006) Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia. Neurobiol Dis 23:374–386
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaun SR (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Ann Biochem 126:131–138
Gumuslu E, Mutlu O, Sunnetci D, Ulak G, Celikyurt I, Cine N, Akar F (2013) The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviours of unpredictable chronic mild stress-exposed mice. Drug Res 63:532–539
Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36:2452–2459
Herbet M, Izdebska M, Piątkowska-Chmiel I, Gawrońska-Grzywacz M, Natorska-Chomicka D, Pawłowski K, Sysa M, Ślaska B, Dudka J (2018) α-Tocopherol ameliorates redox equilibrium and reduces inflammatory response caused by chronic variable stress. BioMed Res Int
Herrero MT, Estrada C, Maatouk L, Vyas S (2015) Inflammation in Parkinson's disease: role of glucocorticoids. Frontiers Neuroanatomy 9:32
Hong H, Kim BS, Im HI (2016) Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders. Int Neurourol J 20:S2
Joëls M, Karst H, Alfarez D, Heine VM, Qin Y, Riel EV, Verkuyl M, Lucassen PJ, Krugers HJ (2004) Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress 7:221–231
Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, Rowan M (2008) Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. Brain 131:651–664
Kouhestani S, Jafari A, Babaei P (2018) Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Reg Res 13:1827
Kumar M, Kaur D, Bansal N (2017) Caffeic acid phenethyl ester (CAPE) prevents development of STZ-ICV induced dementia in rats. Pharmacogn Mag 13:S10
Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR, Butterfield DA (2001) The glial glutamate transporter, GLT-1, is oxidatively modified by 4‐hydroxy‐2‐nonenal in the Alzheimer's disease brain: the role of Aβ1–42. J Neurochem 78:413–416
Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L (2017) Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxid Med Cell Longev
Lovell MA, Markesbery WR (2001) Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol 58:392–396
Lucassen PJ, Heine VM, Muller MB, van der Beek EM, Wiegant VM, Ron De Kloet E, Joels M, Fuchs E, Swaab DF, Czeh B (2006) Stress, depression and hippocampal apoptosis. CNS & Neurological Disorders-Drug Targets. Curr Drug Targets-CNS Neurol Disord 5:531–546
MacPherson A, Dinkel K, Sapolsky R (2005) Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hippocampal cultures. Exp Neurol 194:376–383
Madrigal JL, Hurtado O, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Bosca L, Leza JC (2002) The increase in TNF-alpha levels is implicated in NF-kappaB activation and inducible nitric oxide synthase expression in brain cortex after immobilization stress. Neuropsychopharmacology 26:155–163
Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35(3):676–692
Maia GH, Quesado JL, Soares JI, do Carmo JM, Andrade PA, Andrade JP, Lukoyanov NV (2014) Loss of hippocampal neurons after kainate treatment correlates with behavioural deficits. PloS one 9:e84722
McEwen BS (2000) The neurobiology of stress: From serendipity to clinical relevance. Brain Res 886:172–189
McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, Nasca C (2015) Mechanisms of stress in the brain. Nature Neurosci 18:1353
Mehta V, Parashar A, Sharma A, Singh TR, Udayabanu M (2017a) Quercetin ameliorates chronic unpredicted stress-mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression. Horm Behav 89:13–22
Mehta V, Parashar A, Udayabanu M (2017b) Quercetin prevents chronic unpredictable stress induced behavioural dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. Physiol Behav 171:69–78
Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimica et Biophysica ACTA 582:67–78
Munhoz C, Garcia-Bueno B, Madrigal J, Lepsch L, Scavone C, Leza J (2008) Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res 41:1037–1046
Murray F, Smith DW, Hutson PH (2008) Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Euro J Pharm 583:115–127
Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nature Neurosci 13:1161
Nicolle MM, Gonzalez J, Sugaya K, Baskerville KA, Bryan D, Lund K, Gallagher M, McKinney M (2001) Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 107:415–431
Okhawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Olonode ET, Aderibigbe AO, Adeoluwa OA, Ajayi AM (2018) Protective Effects of Morin Hydrate on Acute Stress-Induced Behavioural and Biochemical Alterations in Mice. Basic Clin Neurosci 9:195
Olonode ET, Aderibigbe AO, Adeoluwa OA, Eduviere AT, Ben-Azu B (2019) Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice. Behav Brain Res 356:518–525
Omidbakhsh R, Rajabli B, Nasoohi S, Khallaghi B, Mohamed Z, Naidu M, Ahmadiani A, Dargahi L (2014) Fingolimod affects gene expression profile associated with LPS-induced memory impairment. Exp Brain Res 232:3687–3696
Patki G, Naimesh S, Fatin A, Farida A, Samina S (2013) Depression, anxiety-like behaviour and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 1539:73–86
Peavy G, David M, Salmon P, Mark WJ, Aaron H, Anthony C, Thomas Gamst TW, LP, Sherry G, Paul J, Mills SK, Douglas G, (2009) Effects of chronic stress on memory decline in cognitively normal and mildly impaired older adults. Am J Psychiatry 166:1384–1391
Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends immunol 27:24–31
Rego AC, Oliveira CR (2003) Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res 28:1563–1574
Rinwa P, Kumar A (2017) Quercetin along with piperine prevents cognitive dysfunction, oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress. Archiv Pharm Res 40:1166–1175
Sousa N, Cerqueira JJ, Almeida OF (2008) Corticosteroid receptors and neuroplasticity. Brain Res Rev 57:561–570
Spencer JP (2010) The impact of fruit flavonoids on memory and cognition. Br J Nutr 104:40–47
Stamouli EC, Politis AM (2016) Pro-inflammatory cytokines in Alzheimer's disease. Psychiatrike Psychiatriki 27:264–275
Tang W, Cheng J, Wang ZY, Chen KY, Han ZM, Wang QH, Yao YY (2016) The synergistic roles of the chronic prenatal and offspring stress exposures in impairing offspring learning and memory. J Alzheimers Dis 53:221–236
Tian R, Hou G, Li D, Yuan T (2014) A possible change process of inflammatory cytokines in the prolonged chronic stress and its ultimate implications for health. Sci World J 2014:780616
Tilbrook AJ, Clarke IJ (2006) Neuroendocrine mechanisms of innate states of attenuated responsiveness of the hypothalamo-pituitary adrenal axis to stress. Front Neuroendocrin 27:285–307
Umukoro S, Aluko OM, Eduviere AT, Owoeye O (2016) Evaluation of adaptogenic-like property of methyl jasmonate in mice exposed to unpredictable chronic mild stress. Brain Res Bull 121:105–114
Venu GJ (2013) Morin Hydrate: Botanical origin, pharmacological activity and its applications: A mini-review. Pharmacogno J 30:1–4
Vyas A, Mitra R, Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818
Weber MD, Godbout JP, Sheridan JF (2017) Repeated social defeat, neuroinflammation, and behaviour: monocytes carry the signal. Neuropsychopharmacology 42:46
Wijeratne SS, Abou-Zaid MM, Shahidi F (2006) Antioxidant polyphenols in almond and its co-products. J Agric Food Chem 54:312–318
Wu A, Ying Z, Gomez-Pinilla F (2010) Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil Neural repair 24:290–298
Zhu S, Shi R, Wang J, Wang JF, Li XM (2014) Unpredictable chronic mild stress not chronic restraint stress induces depressive behaviours in mice. Neuroreport 25:1151–1155
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The Authors appreciate Dr. O.O. Aina of the Department of Veterinary Anatomy and Dr T. Jarikre of the Department of Veterinary Pathology for their individual inputs in the course of the study.
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Elizabeth, A., Adegbuyi, A., Olusegun, A. et al. Morin hydrate attenuates chronic stress-induced memory impairment and degeneration of hippocampal subfields in mice: The role of oxidative, nitrergic and neuroinflammatory pathways. Metab Brain Dis 35, 1145–1156 (2020). https://doi.org/10.1007/s11011-020-00595-2
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DOI: https://doi.org/10.1007/s11011-020-00595-2