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Histological and imunohistochemical alterations of hippocampus and prefrontal cortex in a rat model of Alzheimer like-disease with a preferential role of the flavonoid “hesperidin”

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Abstract

Alzheimer’s disease (AD) is a chronic age-related neurodegenerative disease characterized by degeneration of the central cholinergic neurons, inflammation and oxidative stress in the basal forebrain, prefrontal cortex and hippocampus. Hesperidin (Hesp) is one of the flavonoids havinganti-inflammatory and anti-oxidative properties in some neurodegerative brain lesions. To investigate the possible neuroprotective role of Hespin an AD-like rat model induced experimentally by Scopolamine (Scop). Forty adult male Sprague Dawley rats were randomly allocated into four groups. Group I—(Control), group II—(Hesp) (supplemented orally with 100 mg/kg Hesp for 28 days), group III—(AD) (injected i.p with 1 mg/kg Scop for 9 days) and group IV—(Hesp/AD). At the end of the experiment, behavioral (Y-maze test) and biochemical analysis were carried out along with histological, immunohistochemical and morphometric studies of the hippocampus and prefrontal cortex. AD rats displayed memory impairment in the behavioural paradigm with a concomitant increase of serum TNF-α and IL-1β, while IL-10 decreased significantly. Also, there was a rise of amyloid beta-42 (Aβ-42), acetylcholinesterase (AChE) activity and malondialdehyde (MDA) together with a decrease of reduced glutathione (GSH) in hippocampal and prefrontal homogenate. In addition, sections of the hippocampus and prefrontal cortex revealed obvious histopathological changes, overexpression of p-Tau protein and glial fibrillary acidic protein (GFAP) with a decrease in the expression of synaptophysin (SYN). Contradictorily, pre-treatment with Hesp offset the spatial memory deficits, redox imbalance, Aβ-42 and AChE over activity as well as preserved the histological architecture and attenuated the raised p-Tau protein and GFAP while upregulated SYN immuoreactivity of AD rats. Collectively, our results highlight the potential mitigating role of Hesp in AD-like state in rats and this may presumably raise the possibility of its future implementation as a prophylactic remedy against AD in humans.

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References

  • Adams SV, Winterer J, Müller W (2004) Muscarinic signaling is required for spike-pairing induction of long-term potentiation at rat Schaffer collateral-CA1 synapses. Hippocampus 14(4):413–416. https://doi.org/10.1002/hipo.10197

    Article  CAS  PubMed  Google Scholar 

  • Anand KS, Dhikav V (2012) Hippocampus in health and disease: an overview. Ann Indian Acad Neurol 15(4):239

    Article  Google Scholar 

  • Anand R, Gill KD, Mahdi AA (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 76:27–50. https://doi.org/10.1016/j.neuropharm.2013.07.004

    Article  CAS  PubMed  Google Scholar 

  • Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99(2):353–370

    Article  CAS  Google Scholar 

  • Association A (2018) 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14(3):367–429

    Article  Google Scholar 

  • Association A (2019) 2019 Alzheimer’s disease facts and figures. Alzheimers Dement 15(3):321–387

    Article  Google Scholar 

  • Bassani TB, Bonato JM, Machado MM, Cóppola-Segovia V, Moura EL, Zanata SM, Vital MA (2018) Decrease in adult neurogenesis and neuroinflammation are involved in spatial memory impairment in the streptozotocin-induced model of sporadic Alzheimer’s disease in rats. Mol Neurobiol 55(5):4280–4296. https://doi.org/10.1007/s12035-017-0645-9

    Article  CAS  PubMed  Google Scholar 

  • Bhuvanendran S, Kumari Y, Othman I, Shaikh MF (2018) Amelioration of cognitive deficit by embelin in a scopolamine-induced Alzheimer’s disease-like condition in a rat model. Front Pharmacol 9:665. https://doi.org/10.3389/fphar.2018.00665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brivanlou IH, Dantzker JL, Stevens CF, Callaway EM (2004) Topographic specificity of functional connections from hippocampal CA3 to CA1. Proc Natl Acad Sci 101(8):2560–2565

    Article  CAS  Google Scholar 

  • Cheong MY, Yun SH, Mook-Jung I, Joo I, Huh K, Jung MW (2001a) Cholinergic modulation of synaptic physiology in deep layer entorhinal cortex of the rat. J Neurosci Res 66(1):117–121

    Article  CAS  Google Scholar 

  • Cheong MY, Yun SH, Mook-Jung I, Joo I, Huh K, Jung MW (2001b) Cholinergic modulation of synaptic physiology in deep layer entorhinal cortex of the rat. J Neurosci Res 66(1):117–121. https://doi.org/10.1002/jnr.1203

    Article  CAS  PubMed  Google Scholar 

  • Christopher MA, Myrick DA, Barwick BG, Engstrom AK, Porter-Stransky KA, Boss JM, Katz DJ (2017) LSD1 protects against hippocampal and cortical neurodegeneration. Nat Commun 8(1):1–13. https://doi.org/10.1038/s41467-017-00922-9

    Article  CAS  Google Scholar 

  • Citron M (2010) Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9(5):387–398

    Article  CAS  Google Scholar 

  • de Andrade Teles RB, Diniz TC, Costa Pinto TC, de Oliveira Júnior RG, Gama e Silva M, de Lavor EM, da Silva Almeida JRG (2018) Flavonoids as therapeutic agents in Alzheimer’s and Parkinson’s diseases: a systematic review of preclinical evidences. Oxid Med Cell Longev. https://doi.org/10.1155/2018/7043213

    Article  PubMed  PubMed Central  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82(1):70–77

    Article  CAS  Google Scholar 

  • Fakhoury M (2018) Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr Neuropharmacol 16(5):508–518

    Article  CAS  Google Scholar 

  • Garman RH (2011) Histology of the central nervous system. Toxicol Pathol 39(1):22–35. https://doi.org/10.1177/0192623310389621

    Article  PubMed  Google Scholar 

  • Giese KP (2009) GSK-3: a key player in neurodegeneration and memory. IUBMB Life 61(5):516–521

    Article  CAS  Google Scholar 

  • Gupta R, Gupta LK, Mediratta PK, Bhattacharya SK (2012) Effect of resveratrol on scopolamine-induced cognitive impairment in mice. Pharmacol Rep 64(2):438–444. https://doi.org/10.1016/S1734-1140(12)70785-5

    Article  CAS  PubMed  Google Scholar 

  • Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, Khachaturian ZS (2018) The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141(7):1917–1933. https://doi.org/10.1093/brain/awy132

    Article  PubMed  PubMed Central  Google Scholar 

  • Ikemura M, Sasaki Y, Giddings JC, Yamamoto J (2012) Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res 26(9):1272–1277

    Article  CAS  Google Scholar 

  • Imbimbo BP, Lombard J, Pomara N (2005) Pathophysiology of Alzheimer’s disease. Neuroimaging Clin 15(4):727–753

    Article  Google Scholar 

  • Iqbal K, Alonso ADC, Chen S, Chohan MO, El-Akkad E, Gong CX, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochimica Et Biophysica Acta (BBA) Mol Basis Dis 1739(2–3):198–210. https://doi.org/10.1016/j.bbadis.2004.09.008

    Article  CAS  Google Scholar 

  • Javed H, Vaibhav K, Ahmed ME, Khan A, Tabassum R, Islam F, Islam F (2015) Effect of hesperidin on neurobehavioral, neuroinflammation, oxidative stress and lipid alteration in intracerebroventricular streptozotocin induced cognitive impairment in mice. J Neurol Sci 348(1–2):51–59

    Article  CAS  Google Scholar 

  • Jawaid T, Shakya AK, Siddiqui HH, Kamal M (2014) Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha. Zeitschriftfür Naturforschung c 69(9–10):407–417

    Article  CAS  Google Scholar 

  • Jeon HJ, Seo MJ, Choi HS, Lee OH, Lee BY (2014) Gelidium elegans, an edible red seaweed, and hesperidin inhibit lipid accumulation and production of reactive oxygen species and reactive nitrogen species in 3T3-L1 and RAW264.7 cells. Phytother Res 28(11):1701–1709. https://doi.org/10.1002/ptr.518

    Article  CAS  PubMed  Google Scholar 

  • Jin J, Maren S (2015) Prefrontal-hippocampal interactions in memory and emotion. Front Syst Neurosci 9:170. https://doi.org/10.3389/fnsys.2015.00170

    Article  PubMed  PubMed Central  Google Scholar 

  • Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM (2017) Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr Neurosci 20(6):360–368

    Article  CAS  Google Scholar 

  • Kakadiya J, Mulani H, Shah N (2010) Protective effect of hesperidin on cardiovascular complication in experimentally induced myocardial infarction in diabetes in rats. J Basic Clin Pharm 1(2):85

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kälin AM, Park M, Chakravarty MM, Lerch JP, Michels L, Schroeder C, Leh SE (2017) Subcortical shape changes, hippocampal atrophy and cortical thinning in future Alzheimer’s disease patients. Front Aging Neurosci 9:38. https://doi.org/10.3389/fnagi.2017.00038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kashyap G, Bapat D, Das D, Gowaikar R, Amritkar RE, Rangarajan G, Ambika G (2019) Synapse loss and progress of Alzheimer’s disease-A network model. Sci Rep 9(1):1–9

    Article  CAS  Google Scholar 

  • Khan S, Shad KF (2020) Neuroprotective effects of curcumin and vitamin D3 on scopolamine-induced learning-impaired rat model of Alzheimer’s disease. In Neurological and Mental Disorders. IntechOpen‏

  • Kim DO, Jeong SW, Lee CY (2003) Antioxidant capacity of phenolic phytochemicals from various cultivars of plums. Food Chem 81(3):321–326. https://doi.org/10.1016/S0308-8146(02)00423-5

    Article  CAS  Google Scholar 

  • Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81(3):302–313. https://doi.org/10.1002/jnr.20562

    Article  CAS  PubMed  Google Scholar 

  • Kumar P, Kumar A (2010) Protective effect of hesperidin and naringin against 3-nitropropionic acid induced Huntington’s like symptoms in rats: possible role of nitric oxide. Behav Brain Res 206(1):38–46. https://doi.org/10.1016/j.bbr.2009.08.028

    Article  CAS  PubMed  Google Scholar 

  • Kwon SH, Kim HC, Lee SY, Jang CG (2009) Loganin improves learning and memory impairments induced by scopolamine in mice. Eur J Pharmacol 619(1–3):44–49. https://doi.org/10.1016/j.ejphar.2009.06.062

    Article  CAS  PubMed  Google Scholar 

  • Lakshmi BVS, Sudhakar M, Prakash KS (2015) Protective effect of selenium against aluminum chloride-induced Alzheimer’s disease: behavioral and biochemical alterations in rats. Biol Trace Elem Res 165(1):67–74

    Article  CAS  Google Scholar 

  • Lalonde R (2002) The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26(1):91–104. https://doi.org/10.1016/S0149-7634(01)00041-0

    Article  CAS  PubMed  Google Scholar 

  • Lee JS, Kim HG, Lee HW, Han JM, Lee SK, Kim DW, Son CG (2015) Hippocampal memory enhancing activity of pine needle extract against scopolamine-induced amnesia in a mouse model. Sci Rep 5(1):1–10

    Google Scholar 

  • Li K, Li J, Zheng J, Qin S (2019) Reactive astrocytes in neurodegenerative diseases. Aging Dis 10(3):664

    Article  CAS  Google Scholar 

  • Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46(6):957–967. https://doi.org/10.1016/j.immuni.2017.06.006

    Article  CAS  PubMed  Google Scholar 

  • Lim JW, Lee J, Pae AN (2020) Mitochondrial dysfunction and Alzheimer’s disease: prospects for therapeutic intervention. BMB Rep 53(1):47

    Article  CAS  Google Scholar 

  • Liu YH, Lee CJ, Chen LC, Lee TL, Hsieh YY, Han CH, Hou WC (2020) Acetylcholinesterase inhibitory activity and neuroprotection in vitro, molecular docking, and improved learning and memory functions of demethyl curcumin in scopolamine-induced amnesia ICR mice. Food Funct 11(3):2328–2338

    Article  CAS  Google Scholar 

  • Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G (2016) Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int. https://doi.org/10.1155/2016/2589276

    Article  PubMed  PubMed Central  Google Scholar 

  • Morrison AS, Lyketsos C (2005) The pathophysiology of Alzheimer’s disease and directions in treatment. Adv Stud Nurs 3(8):256–270

    Google Scholar 

  • Nijveldt RJ, Van Nood ELS, Van Hoorn DE, Boelens PG, Van Norren K, Van Leeuwen PA (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74(4):418–425. https://doi.org/10.1093/ajcn/74.4.418

    Article  CAS  Google Scholar 

  • Odukoya O, Sofidiya M, Ilori O, Gbededo M, Ajadotuigwe J, Olaleye O, Brinkhaus B (1994) Malondialdehyde determination as index of lipid peroxidation. Int J Biol Chem 3:281–285

    Google Scholar 

  • Pagnier GJ, Kastanenka KV, Sohn M, Choi S, Choi SH, Soh H, Bacskai BJ (2018) Novel botanical drug DA-9803 prevents deficits in Alzheimer’s mouse models. Alzheimer’s Res Ther 10(1):1–13

    Article  Google Scholar 

  • Pattanashetti LA, Taranalli AD, Parvatrao V, Malabade RH, Kumar D (2017) Evaluation of neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia in rats. Indian J Pharmacol 49(1):60

    CAS  PubMed  PubMed Central  Google Scholar 

  • Paul CM, Magda G, Abel S (2009) Spatial memory: theoretical basis and comparative review on experimental methods in rodents. Behav Brain Res 203(2):151–164. https://doi.org/10.1016/j.bbr.2009.05.022

    Article  PubMed  Google Scholar 

  • Perl DP (2010) Neuropathology of Alzheimer’s disease. Mt Sinai J Med 77(1):32–42

    Article  Google Scholar 

  • Popović M, Caballero-Bleda M, Benavente-García O, Castillo J (2014) The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats. J Psychopharmacol 28(5):498–501. https://doi.org/10.1177/0269881113512040

    Article  CAS  PubMed  Google Scholar 

  • Poulakis K, Pereira JB, Mecocci P, Vellas B, Tsolaki M, Kłoszewska I, Westman E (2018) Heterogeneous patterns of brain atrophy in Alzheimer’s disease. Neurobiol Aging 65:98–108

    Article  Google Scholar 

  • Rahnama S, Rabiei Z, Alibabaei Z, Mokhtari S, Rafieian-Kopaei M, Deris F (2015) Anti-amnesic activity of Citrus aurantium flowers extract against scopolamine-induced memory impairments in rats. Neurol Sci 36(4):553–560

    Article  Google Scholar 

  • Raza SS, Khan MM, Ahmad A, Ashafaq M, Khuwaja G, Tabassum R, Islam F (2011) Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res 1420:93–105. https://doi.org/10.1016/j.brainres.2011.08.047

    Article  CAS  PubMed  Google Scholar 

  • Rybakowski JK (2018) Lithium in Alzheimer’s disease: experimental, epidemiological and clinical findings. In: Dorszewska J, Kozubski W (eds) Alzheimer’s disease. The 21st century challenge. IntechOpen, London, pp 79–89

    Google Scholar 

  • Salem HRA, El-Raouf AA, Saleh EM, Shalaby KA (2012) Influence of hesperidin combined with Sinemet on genetical and biochemical abnormalities in rats suffering from Parkinson’s disease. Life Sci J 9(4):930–945

    Google Scholar 

  • Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205

    Article  CAS  Google Scholar 

  • Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Wharton SB (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31(4):578–590. https://doi.org/10.1016/j.neurobiolaging.2008.05.015

    Article  CAS  PubMed  Google Scholar 

  • Suvarna KS, Layton C, Bancroft JD (2018) Bancroft’s theory and practice of histological techniques. E-Book, Elsevier Health Sciences. Churchill Livingstone

  • Tabatabaei-Jafari H, Shaw ME, Walsh E, Cherbuin N et al (2019) Regional brain atrophy predicts time to conversion to Alzheimer’s disease, dependent on baseline volume. Neurobiol Aging 83:86–94

    Article  Google Scholar 

  • Talesa VN (2001) Acetylcholinesterase in Alzheimer’s disease. Mech Ageing Dev 122(16):1961–1969. https://doi.org/10.1016/S0047-6374(01)00309-8

    Article  CAS  PubMed  Google Scholar 

  • Tamilselvam K, Braidy N, Manivasagam T, Essa MM, Prasad NR, Karthikeyan S, Guillemin GJ (2013) Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson’s disease. Oxid Med Cell Longev. https://doi.org/10.1155/2013/102741

    Article  PubMed  PubMed Central  Google Scholar 

  • Uddin MS, Kabir MT, Al Mamun A, Barreto GE, Rashid M, Perveen A, Ashraf GM (2020) Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease. Int Immunopharmacol 84:106479. https://doi.org/10.1016/j.intimp.2020.106479

    Article  CAS  PubMed  Google Scholar 

  • Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016) The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 18(5):421–430

    Article  Google Scholar 

  • Wall PM, Messier C (2002) Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory. Psychopharmacology 160(3):233–244

    Article  CAS  Google Scholar 

  • Wan T, Wang Z, Luo Y, Zhang Y, He W, Mei Y, Huang Y (2019) FA-97, a new synthetic caffeic acid phenethyl ester derivative, protects against oxidative stress-mediated neuronal cell apoptosis and scopolamine-induced cognitive impairment by activating Nrf2/HO-1 signaling. Oxid Med Cell Longev. https://doi.org/10.1155/2019/8239642

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu XL, Piña-Crespo J, Zhang YW, Chen XC, Xu HX (2017) Tau-mediated neurodegeneration and potential implications in diagnosis and treatment of Alzheimer’s disease. Chin Med J 130(24):2978

    Article  CAS  Google Scholar 

  • Zhang J, Zhen YF, Song LG, Kong WN, Shao TM, Li X, Chai XQ (2013) Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res 244:70–81. https://doi.org/10.1016/j.bbr.2013.01.037

    Article  CAS  PubMed  Google Scholar 

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Mandour, D.A., Bendary, M.A. & Alsemeh, A.E. Histological and imunohistochemical alterations of hippocampus and prefrontal cortex in a rat model of Alzheimer like-disease with a preferential role of the flavonoid “hesperidin”. J Mol Histol 52, 1043–1065 (2021). https://doi.org/10.1007/s10735-021-09998-6

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