Soybean isoflavone ameliorates cognitive impairment, neuroinflammation, and amyloid β accumulation in a rat model of Alzheimer’s disease

  • Amina E. Essawy
  • Heba Mohamed AbdouEmail author
  • Hania M. Ibrahim
  • Najya M. Bouthahab
Research Article


Oxidative stress and neuroinflammatory changes appear to be the early events involved in AD’s development and progression. The present study was designed to assess the effect of soybean isoflavone extract (SIFE) against colchicine-induced cognitive dysfunction and oxidative stress in male rats.

Fifty adult male Wistar albino rats were divided into five groups: control, ACSF-treated group, soybean isoflavones (SIF)-treated group, colchicine (COL)-treated group, and SIF + COL-treated group. We found that an intracerebroventricular (icv) injection of a single dose of colchicine (7.5 μg/rat bilaterally) resulted in learning deficits in rats subjected to the Morris water maze task associated with marked oxidative damage and decreased acetyl cholinesterase (AChE) activity. In addition, COL caused significant increase in amyloid beta peptide 1-42 (β, amyloid 1-42) interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), cyclooxygenase-2 (COX-2) and TNF-α genes expression in the brain, and glial fibrillary acidic protein (GFAP) in cortical astrocytes in the brain cortex.

Treatment with SIFE (80 mg/kg b.wt) daily for 14 days followed by a single dose of COL significantly reduced the elevated oxidative stress parameters and restored the reduced antioxidant activities. Besides, the administration of SIFE reversed the overproduction of β, amyloid 1-42, pro-inflammatory cytokines, and GFAP in the brain. The obtained results were confirmed by histological observations that clearly indicate a neuroprotective effect of SIF against AD.


Alzheimer’s disease Colchicine Soybean isoflavone Rat 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Aras AB, Guven M, Akman T, Alacam H, Kalkan Y, Silan C, Cosar M (2015) Genistein exerts neuroprotective effect on focal cerebral ischemia injury in rats. Inflammation 38:1311–1321Google Scholar
  2. Baba NA, Raina R, Verma PK, Sultana M, Prawez S, Nisar NA (2013) Toxic effects of fluoride and chlorpyrifos on antioxidant parameters in rats: protective effects of vitamins C and E. Fluoride 46:73–79Google Scholar
  3. Bagchi A (2016) Protective effect of epigallocatechin-3-gallate (EGCG) the major tea polyphenolic, against intracerebroventricularly colchicine induced oxidative damage production in brain and cognitive dysfunction in mice. Alzheimer’s Dis Parkinsonism 6:2161–0460Google Scholar
  4. Bagheri M, Rezakhani A, Nyström S, Turkina MV, Roghani M, Hammarström P, Mohseni S (2013) Amyloid beta1-40-induced astrogliosis and the effect of genistein treatment in rat: a three-dimensional confocal morphometric and proteomic study. PLoS One 8:1–14Google Scholar
  5. Bhatt PC, Pathak S, Kumar V, Panda BP (2017) Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer‘s disease by fermented soybean nanonutraceutical. Inflammopharmacology 26(3):1–14Google Scholar
  6. Bondan EF, Martins MF, Viani FC (2013) Decreased astrocytic GFAP expression in streptozotocin-induced diabetes after gliotoxic lesion in the rat brainstem. Arq Bras Endocrinol Metabol 57(6):431–436Google Scholar
  7. Brigelius-Flohé R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta Gen Subj 1830:3289–3303Google Scholar
  8. Cha YS, Park Y, Lee M, Chae SW, Park K, Kim Y, Lee HS (2014) Doenjang, a Korean fermented soy food, exerts antiobesity and antioxidative activities in overweight subjects with the PPAR-γ2 C1431T polymorphism: 12-week, double-blind randomized clinical trial. Med Food 17:119–127Google Scholar
  9. Chiu SC, Yang NS, (2007) Inhibition of tumor necrosis factor-alpha through selective blockade of Pre-mRNA splicing by shikonin. Mol Pharmacol.;71(6):1640–5Google Scholar
  10. Chiu DT, Stults FH, Tappel AL (1976) Purification and properties of rat lung soluble glutathione peroxidase. Biochim Biophys Acta Enzymol 445:558–566Google Scholar
  11. Devi KP, Shanmuganathan B, Manayi A, Nabavi SF, Nabavi SM (2017) Molecular and therapeutic targets of genistein in Alzheimer’s disease. Mol Neurobiol 54:7028–7041Google Scholar
  12. Ding BJ, Ma WW, He LL, Zhou X, Yuan LH, Yu HL, Feng JF, Xiao R (2011) Soybean isoflavone alleviates β-amyloid 1-42 induced inflammatory response to improve learning and memory ability by down regulation of Toll-like receptor 4 expression and nuclear factor-κB activity in rats. Int J Dev Neurosci 29:537–542Google Scholar
  13. Ding J, Yu HL, Ma WW, Xi YD, Zhao X, Yuan LH, Feng JF, Xiao R (2013) Soy isoflavone attenuates brain mitochondrial oxidative stress induced by beta-amyloid peptides 1–42 injection in lateral cerebral ventricle. Neurosci Res 91:562–567Google Scholar
  14. Drury RA, Wallington EA (1980) Carleton's Histological Technique (5thed.) Oxford University Press. Oxford New York Toronto 188-189(237240):290–291Google Scholar
  15. Ellman GL, Courtney KD, Anders VJ, Featherstone RM (1961) A new rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95Google Scholar
  16. Ferguson-Smith AC, Chen YF, Newman MS, May LT, Sehgal PB, Ruddle FH (1988) Regional localization of the interferon-β2B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21. Genomics 2:203–208Google Scholar
  17. Ganesh P, Karthikeyan R, Muthukumaraswamy A, Anand J (2017) A potential role of periodontal inflammation in Alzheimer’s disease: a review. Oral Health Prev Dent 15:7–12Google Scholar
  18. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases.The first enzymatic step in mercapturic acid formation. Biol Chem 249:7130–7139Google Scholar
  19. Hedayati M, Yazdanparast R, Azizi F (2001) Determination of human tumor necrosis factor α by a highly sensitive enzyme immunoassay. Biochem Biophys Res Commun 289:295–298Google Scholar
  20. Jollow DJ, Mitchell JR, Zampaglione NA, Gillette JR (1974) Bromobenzene-induced liver necrosis.Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169Google Scholar
  21. Khurana S, Jain S, Mediratta PK, Banerjee BD, Sharma KK (2012) Protective role of curcumin on colchicine-induced cognitive dysfunction and oxidative stress in rats. Hum Exp Toxicol 31:686–697Google Scholar
  22. Kumar A, Seghal N, Naidu PS, Padi SS, Goyal R (2007) Colchicines induced neurotoxicity as an animal model of sporadic dementia of Alzheimer’s type. Pharmacol Rep 59:274–283Google Scholar
  23. Kumar A, Dogra S, Prakash A (2009) Neuroprotective effects of Centella asiatica against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress. Int J Alzheimers Dis 2009:1–8. Google Scholar
  24. Kwon Y (2014) Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies. Food Sci Nutr 2:613–622Google Scholar
  25. Legos JJ, Tuma RF, Barone FC (2002) Pharmacological interventions for stroke: failures and future. Expert Opin Investig Drugs 11(5):603–614Google Scholar
  26. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, Barberger-Gateau P (2007) Flavonoid intake and cogni tive decline over a 10-year period. Am J Epidemiol 15(165(12)):1364–1371Google Scholar
  27. Lim KL, Tay A, Nadarajah VD, Mitra NK (2011) The effect of consequent exposure of stress and dermal application of low doses of chlorpyrifos on the expression of glial fibrillary acidic protein in the hippocampus of adult mice. Occup Med Toxicol 6:1–9Google Scholar
  28. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25:402–408Google Scholar
  29. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. Biol Chem 193:265275Google Scholar
  30. Maiti P, Paladugu L, Dunbar GL (2018) Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer’s disease. BMC Neurosci 19(1):7. Google Scholar
  31. Malkiewicz K, Koteras M, Folkesson R, Brzezinski J, Winblad B, Szutowski M, Benedikz E (2006) Cypermethrin alters glial fibrillary acidic protein levels in the rat brain. Environ Toxicol Pharmacol 21:51–55Google Scholar
  32. Mansour SA, Moss AT (2010) Oxidative damage, biochemical and histopathological alterations in rats exposed to chlorpyrifos and the antioxidant role of zinc. Pestic Biochem Physiol 96:14–23Google Scholar
  33. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. Biol Chem 247:3170–3175Google Scholar
  34. Mohamed AR, Soliman GY, Ismail CA, Mannaa HF (2015) Neuroprotective role of vitamin D3 in colchicine-induced Alzheimer’s disease in rats. Alexandria J Med 51:127–136Google Scholar
  35. Montogomery HA, Dymock JF (1961) The determination of nitrite in water: colorimetric method of nitric oxide assay. Analyst 86:414–416Google Scholar
  36. Nimse SB, Pal D (2015) Free radicals, natural antioxidants, and their reaction mechanisms. RSC Adv 5:27986–28006Google Scholar
  37. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxidation in animal tissues by thiobarbituric acid reaction. Ann Biochem 95:351–358Google Scholar
  38. Park YJ, Ko JW, Jeon S, Kwon YH (2016) Protective effect of genistein against neuronal degeneration in ApoE−/− mice fed a high-fat diet. Nutrients 8:1–11Google Scholar
  39. Qian Y, Guan T, Huang M, Cao L, Li Y, Cheng H, Jin H, Yu D (2012) Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen inducedNF-κB activation in a cerebral ischemia mouse model. Neurochem Int 60:759–767Google Scholar
  40. Roy C, Das SK (2013) Role of Moringa oleifera on brain electrical activity in colchicine induced experimental rat model of Alzheimer’s disease: possible involvement of antioxidants. Int J Curr Pharm Res 5:40–45Google Scholar
  41. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G (2017) Neuroinflammation pathways: a general review. Int J Neurosci 127:624–633Google Scholar
  42. Sharma VK (2010) Experimental models for alzheimer’s disease: a mechanistic view. Int J Pharm Sci Res 1:13–22Google Scholar
  43. Sil S, Goswami AR, Dutta G, Ghosh T (2014) Effects of naproxen on immune responses in a colchicine-induced rat model of Alzheimer’s disease. Neuroimmunomodulation 21:304–321Google Scholar
  44. Sil S, Ghosh R, Sanyal M, Guha D, Ghosh T (2016) A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection. Immunotoxicology 13:181–190Google Scholar
  45. Sovrea AS, Bosca AB, Georgiu C, Constantin AM, Ben AM, Gheban D (2014) The diagnostic value of immunohistochemistry and silver impregnation techniques for characterization of normal, reactive and tumoral astrocytes. Romanian J Morphol Embryol 55:525–538Google Scholar
  46. Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A (2011) Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci 31:4475–4483Google Scholar
  47. Torres LL, Quaglio NB, de Souz GT, Garcia RT, Dati LM, Moreira WL et al (2011) Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 26(1):59–68Google Scholar
  48. Unno K, Konishi T, Nakagawa A, Narita Y, Takabayashi F, Okamura H, Hara A, Yamamoto H, Iguchi K, Hoshino M, Yasui K (2015) Cognitive dysfunction and amyloid β accumulation are ameliorated by the ingestion of green soybean extract in aged mice. J Funct Foods 14:345–353Google Scholar
  49. Varinska L, Gal P, Mojzisova G, Mirossay L, Mojzis J (2015) Soy and breast cancer: focus on angiogenesis. Int J Mol Sci 16:11728–11749Google Scholar
  50. Velho S, Marques-Vidal P, Baptista F, Camilo ME (2008) Dietary intake adequacy and cognitive function in free-living active elderly: a cross-sectional and short-term prospective study. Clin Nutr 27(1):77–86Google Scholar
  51. Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxidative Med Cell Longev 2013:1–12. Google Scholar
  52. Wang WY, Tan MS, Yu JT, Tan L (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3:136–145Google Scholar
  53. Wu YC, Zheng D, Sun JJ, Zou ZK, Ma ZL (2015) Meta-analysis of studies on breast cancer risk and diet in Chinese women. Int J Clin Exp Med 8:73–85Google Scholar
  54. Yoon G, Park S (2014) Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr Res Pract 8:618–624Google Scholar
  55. Yu J, Bi X, Yu B, Chen D (2016) Isoflavones: anti-inflammatory benefit and possible caveats. Nutrients 8:361–366Google Scholar
  56. Zhai X, Lin M, Zhang F, Hu Y, Xu X, Li Y, Liu K, Ma X, Tian X, Yao J (2013) Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco-2 cells. Mol Nutr Food Res 57:249–259Google Scholar
  57. Zhang L, Fang Y, Lian Y, Chen Y, Wu T, Zheng Y, Zong H, Sun L, Zhang R, Wang Z, Xu Y (2015) Brain-derived neurotrophic factor ameliorates learning deficits in a rat model of Alzheimer’s disease induced by Aβ1-42. PLoS One 10:1–14Google Scholar
  58. Zhao Z, Ho L, Wang J, Qin W, Festa ED, Mobbs C, Hof P, Rocher A, Masur S, Haroutunian V, Pasinetti GM (2005) Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance-associated promotion of Alzheimer’s disease β-amyloid neuropathology. FASEB J 19:2081–2082Google Scholar
  59. Zheng Z, Sabirzhanov B, Keifer J (2010) Oligomeric amyloid-β inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning. J Biol Chem 285:34708–34717Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Amina E. Essawy
    • 1
  • Heba Mohamed Abdou
    • 1
    Email author
  • Hania M. Ibrahim
    • 1
  • Najya M. Bouthahab
    • 2
  1. 1.Department of Zoology, Faculty of ScienceAlexandria UniversityAlexandriaEgypt
  2. 2.Department of Zoology, Faculty of ScienceOmar Al Mukhtar UniversityAl BaydaLibya

Personalised recommendations