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Gingko biloba abrogate lead-induced neurodegeneration in mice hippocampus: involvement of NF-κB expression, myeloperoxidase activity and pro-inflammatory mediators

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Abstract

Neuroimmune alterations have important implication in the neuropsychiatric symptoms and biochemical changes associated with lead-induced neurotoxicity. It has been suggested that inhibition of neuroinflammatory-mediated lead-induced neurotoxicity by phytochemicals enriched with antioxidant activities would attenuate the deleterious effects caused by lead. Hence, this study investigated the neuroinflammatory mechanism behind the effect of Ginkgo biloba supplement (GB-S) in lead-induced neurotoxicity in mice brains. Mice were intraperitoneally pretreated with lead acetate (100 mg/kg) for 30 min prior the administration of GB-S (10 and 20 mg/kg, i.p.) and ethylenediaminetetraacetic acid (EDTA) (50 mg/kg, i.p.) for 14 consecutive days. Symptoms of neurobehavioral impairment were evaluated using open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST) respectively. Thereafter, mice brain hippocampi were sectioned for myeloperoxidase activity (MPO), pro-inflammatory cytokine (TNF-α and IL-6) estimation and inflammatory protein (NF-κB) expression. Furthermore, histomorphormetric studies (Golgi impregnation and Cresyl violet stainings) were carried out. GB-S (10 and 20 mg/kg) significantly restores neurobehavioral impairments based on improved locomotion, reduced anxiety- and depressive-like behavior. Moreover, GB-S reduced the MPO activity, inhibits TNF-α, IL-6 release, and downregulates NF-κB immunopositive cell expression in mice hippocampus. Histomorphometrically, GB-S also prevents the loss of pyramidal neuron in the hippocampus. The endpoint of this findings suggest that GB-S decreases neuropsychiatric symptoms induced by lead acetate through mechanisms related to inhibition of release of pro-inflammatory mediators and suppression of hippocampal pyramidal neuron degeneration in mice.

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References

  1. Fenn AM, Henry CJ, Huang Y, Dugan A, Godbout JP (2012) Lipopolysaccharide-induced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav Immun 26:766–777

    CAS  PubMed  Google Scholar 

  2. Elmore MR, Najafi AR, Koike MA et al (2014) Colonystimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380–397

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Umukoro S, Iwalewa EO (2019) 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

    Google Scholar 

  4. Wopara I, Modo EU, Adebayo OG, Mobisson SK, Nwigwe JO, Ogbu PI, Nwankwo VU, Ejeawa CU (2021) Anxiogenic and memory impairment effect of food color exposure: upregulation of oxido-neuroinflammatory markers and acetyl-cholinestrase activity in the prefrontal cortex and hippocampus. Heliyon 7(3):e06378. https://doi.org/10.1016/j.heliyon.2021.e06378

    Article  PubMed  PubMed Central  Google Scholar 

  5. Umukoro S, Ben-Azu B, Ajayi AM, Adebesin A, Emokpae O (2020) Cymbopogon citratus aqueous leaf extract attenuates neurobehavioral and biochemical changes induced by social defeat stress in mice. Chin Herb Med 12(3):303–309

    Google Scholar 

  6. Cermenati G, Mitro N, Audano M, Melcangi RC, Crestani M, De Fabiani E (1851) Caruso D (2015) Lipids in the nervous system: from biochemistry and molecular biology to patho-physiology. Biochim Biophys Acta 1:51–60

    Google Scholar 

  7. Schmitt F, Hussain G, Dupuis L, Loeffler JP, Henriques A (2014) A plural role for lipids in motor neuron diseases: energy, signalling and structure. Front Cell Neurosci 8:25

    PubMed  PubMed Central  Google Scholar 

  8. Müller CP, Reichel M, Mühle C, Rhein C, Gulbins E (1851) Kornhuber J (2015) Brain membrane lipids in major depression and anxiety disorders. Biochim Biophys Acta 8:1052–1065

    Google Scholar 

  9. Singh PK, Rawat A, Dixit RK, Kumar P, Nath R (2017) Behavioral and neurochemical effects of omega-3 fatty acids against lead acetate exposure in male Wistar rats: an experimental study. Int J Curr Res 7:20936–20944

    Google Scholar 

  10. Adebayo OG, Wopara I, Ben-Azu B, Aduema W, Adebayo OR, Nicodemus OU (2020) Acute Lead (II) Acetate 3-hydrate neurotoxicity alters neurocognition and induced depressive-like behavior via 5-hydroxytryphtamine, neurohormone melatonin and (Na+, K+)-ATPase activity in female Wistar rats. Asian J Biotechnol Genet Eng 20:31–40

    Google Scholar 

  11. Atuadu V, Benneth BA, Oyem J, Esom E, Mba C, Nebo K, Ezemeka G, Anibeze C (2020) Adansonia digitata L. leaf extract attenuates lead-induced cortical histoarchitectural changes and oxidative stress in the prefrontal cortex of adult male Wistar rats. Drug Metab Pers Ther. https://doi.org/10.1515/dmdi-2020-0116

  12. Zare MF, Niknazar S, Yadegari M, Akbari FA, Pirmoradi Z, Khaksari M (2020) Carvacrol reduces hippocampal cell death and improves learning and memory deficits following lead-induced neurotoxicity via antioxidant activity. Naunyn Schmiedebergs Arch Pharmacol 393(7):1229–1237. https://doi.org/10.1007/s00210-020-01866-6

    Article  CAS  Google Scholar 

  13. Baranowska-bosiacka I, Strużyńska L, Gutowska I, Machalińska A, Kolasa A, Kłos P, Czapski G, Kurzawski M, Prokopowicz A, Marchlewicz M (2013) Perinatal exposure to lead induces morphological, ultrastructural andmolecular alterations in the hippocampus. Toxicology 303:187–200

    CAS  PubMed  Google Scholar 

  14. Verma S, Sharma S, Ranawat P, Nehru B (2020) Modulatory effects of Ginkgo biloba against amyloid aggregation through induction of heat shock proteins in aluminium induced neurotoxicity. Neurochem Res 45:465

    CAS  PubMed  Google Scholar 

  15. Chen M, Zou W, Chen M, Cao L, Ding J, Xiao W, Hu G (2018) Ginkgolide K promotes angiogenesis in a middle cerebral artery occlusion mouse model via activating JAK2/STAT3 pathway. Eur J Pharmacol 833:221–229

    CAS  PubMed  Google Scholar 

  16. Yang X, Zheng T, Hong H, Cai N, Zhou X, Sun C, Wu L, Liu S, Zhao Y, Zhu L, Fan M, Zhou X, Jin F (2018) Neuroprotective effects of Ginkgo biloba extract and ginkgolide B against oxygen-glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model. Front Med 12:307–318

    PubMed  Google Scholar 

  17. Singh B, Kaur P, Gopichand C, Singh BD, Ahuja PS (2008) Biology and chemistry of Ginkgo biloba. Fitoterapia 79:401–418

    CAS  PubMed  Google Scholar 

  18. Liao HJ, Zheng YF, Li HY, Peng GP (2011) Two new ginkogolides from leaves of Ginkgo biloba. Planta Med 77:1818–1821

    CAS  PubMed  Google Scholar 

  19. Ude C, Schubert-Zsilavecz M, Wurglics M (2013) Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet 52(9):727–749

    CAS  PubMed  Google Scholar 

  20. Osman NM, Amer AS, Abdelwahab S (2016) Effects of Ginko biloba leaf extract on the neurogenesis of the hippocampal dentate gyrus in the elderly mice. Anat Sci Int 91:280–289

    PubMed  Google Scholar 

  21. Sadeghinejada M, Soltanib Z, Afzalpoura ME, Khaksaric M, Pourranjbard M (2019) What is the combined effect of intense intermittent exercise and Ginkgo biloba plant on the brain neurotrophic factors levels, and learning and memory in young rats? Pharmacol Rep 71:503–508

    Google Scholar 

  22. Yao J, Qiao H, Jin Z, Wang R, Huang H, Fang L, Chen Y, Tai K, Doeppner TR, Chen Z, Kuchta K (2020) Ginkgo biloba and its constituent 6-hydroxykynurenic-acid as well as its proanthocyanidins exert neurorestorative effects against cerebral ischemia. Planta Med 86(10):696–707

    CAS  PubMed  Google Scholar 

  23. Yapar K, Cavusoglu K, Oruc E, Yalcin E (2010) Protective role of Ginkgo biloba against hepatotoxicity and nephrotoxicity in uranium-treated mice. J Med Food 13(1):179–188

    CAS  PubMed  Google Scholar 

  24. Kaur S, Chhabra R, Nehru B (2013) Ginkgo biloba extract attenuates hippocampal neuronal loss and cognitive dysfunction resulting from trimethyltin in mice. Phytomed 20(2):178–186

    CAS  Google Scholar 

  25. Abd-Elhady RM, Elsheikh AM, Khalifa AE (2013) Ani-amnesic properties of Ginkgo biloba extract on impaired memory function induced by aluminum in rats. Int J Dev Neurosci 31(7):598–607

    CAS  PubMed  Google Scholar 

  26. Yallapragada RP, Velaga MK (2015) Effect of Ginkgo biloba extract on lead-induced oxidative stress in different regions of rat brain. J Environ Pathol Toxicol Oncol 34(2):161–173

    PubMed  Google Scholar 

  27. National Institute of Health Guide for the Care and Use of Laboratory Animals (1996) Washington DC: National Academic Press

  28. Oshio LT, Ribeiro CCT, Marques RM, Guerra MO, Pinto da Matta SL, de Paula Reis JE, Sá RCS, Campos LV, Peters VM (2015) Effect of Ginkgo biloba extract on sperm quality, serum testosterone concentration and histometric analysis of testes from adult Wistar rats. J Med Plants Res 9(5):122–131. https://doi.org/10.5897/JMPR2015.5730

    Article  CAS  Google Scholar 

  29. Ekici Gunay N, Muhtaroglu S, Bedirli A (2018) Administration of Ginkgo biloba extract (EGb761) alone and in combination with FK506 promotes liver regeneration in a rat model of partial hepatectomy. Balkan Med J 35(2):174–180

    PubMed  PubMed Central  Google Scholar 

  30. Nishimon S, Yamaguchi M, Muraki H, Sakai N, Nishino S (2020) Intraperitoneal injection of ginkgolide B, a major active compound of Ginkgo biloba, dose-dependently increases the amount of wake and decreases non-rapid eye movement sleep in C57BL/6 mice. Neurosci Lett 722:134832

    CAS  PubMed  Google Scholar 

  31. Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504

    CAS  PubMed  Google Scholar 

  32. Izídio GS, Lopes DM, Spricigo L Jr, Ramos A (2005) Common variations in the pretest environment influence genotypic comparisons in models of anxiety. Genes Brain Behav 4(7):412–419. https://doi.org/10.1111/j.1601-183X.2005.00121.x

    Article  PubMed  Google Scholar 

  33. Dereli FTG, Ilhan M, Akkol EK (2018) Discovery of new antidepressant agents: in vivo study on Anthemis wiedemanniana Fisch. & Mey. J Ethnopharmacol 226:11–16

    Google Scholar 

  34. Handley SL, Mithani S (1984) Effects of a-adrenoreceptor agonists and antagonists in a maze-exploration model of ‘fear’-motivated behavior. Naunyn-Schmeide-berg′s Arch Pharmacol 327(1):1–5

    CAS  Google Scholar 

  35. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167

    CAS  PubMed  Google Scholar 

  36. Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177(2):751–766

    CAS  PubMed  Google Scholar 

  37. Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209

    CAS  PubMed  Google Scholar 

  38. Angulo E, Fernandez JA, Merchan M, Molina (1996) A reliable method for Golgi staining of retina and brain slices. J Neurosci Methods 66:55–59

    CAS  PubMed  Google Scholar 

  39. Edelstein AD, Mark AT, Nenad A, Henry P, Ronald DV, Nico S (2014) Advanced methods of microscope control using μManager software. J Biol Methods 1:e10

    PubMed  Google Scholar 

  40. Wu A, Liu Y (2000) Apoptotic cell death in rat brain following deltamethrin treatment. Neurosci Lett 279:85–88

    CAS  PubMed  Google Scholar 

  41. Peng C, Trojanowski JQ, Lee VM (2020) Protein transmission in neurodegenerative disease. Nat Rev Neurol 16(4):199–212

    CAS  PubMed  Google Scholar 

  42. Feng YK, Wu QL, Peng YW, Liang FY, You HJ, Feng YW, Li G, Li XJ, Liu SH, Li YC, Zhang Y (2020) Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice. J Neuroinflammation 17(1):1–2

    Google Scholar 

  43. Dardiotis E, Rikos D, Siokas V, Aloizou AM, Tsouris Z, Sakalakis E, Brotis AG, Bogdanos DP, Hadjigeorgiou GM (2020) Assessment of TREM2 rs75932628 variant’s association with Parkinson’s disease in a Greek population and meta-analysis of current data. Int J Neurosci 20:1–5

    Google Scholar 

  44. Peng X, Li C, Yu W, Liu S, Cong Y, Fan G, Qi S (2020) Propofol attenuates hypoxia-induced inflammation in BV2 microglia by inhibiting oxidative stress and NF-κB/Hif-1α signaling. Biomed Res Int 2020:8978704

  45. Srejovic I, Selakovic D, Jovicic N, Jakovljević V, Lukic ML, Rosic G (2020) Galectin-3: roles in neurodevelopment, neuroinflammation, and behavior. Biomolecules 10(5):798

    CAS  PubMed Central  Google Scholar 

  46. Azogu-Sepe I, Plamondon H (2021) Stress responsiveness of BDNF/TrkB signaling in the neuroendocrine system and future implications. In: Stress: Genetics, Epigenetics and Genomics 145–158

  47. Gold PW (2015) The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 20:32–47

    CAS  PubMed  Google Scholar 

  48. Welcome MO (2020) Cellular mechanisms and molecular signaling pathways in stress-induced anxiety, depression, and blood–brain barrier inflammation and leakage. Inflammopharmacology 28(3):643–665

    PubMed  Google Scholar 

  49. McEwen BS, Gray JD, Nasca C (2015) Recognizing resilience: learning from the effects of stress on the brain. Neurobiol Stress 1:1–11

    PubMed  Google Scholar 

  50. Kumari P, Wadhwa M, Chauhan G, Alam S, Roy K, Jha PK, Kishore K, Ray K, Nag TC, Panjwani U (2020) Hypobaric hypoxia induced fear and extinction memory impairment and effect of Ginkgo biloba in its amelioration: behavioral, neurochemical and molecular correlates. Behav Brain Res 387:112595

    CAS  PubMed  Google Scholar 

  51. Davies MJ, Hawkins CL (2020) The role of myeloperoxidase in biomolecule modification, chronic inflammation, and disease. Antioxid Redox Signal 32(13):957–981

    CAS  PubMed  Google Scholar 

  52. Chen S, Chen H, Du Q, Shen J (2020) Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds. Front Physiol 11:433

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Volkman R, Ben-Zur T, Kahana A, Garty BZ, Offen D (2019) Myeloperoxidase deficiency inhibits cognitive decline in the 5XFAD mouse model of Alzheimer’s disease. Front Neurosci 13:990. https://doi.org/10.3389/fnins.2019.00990

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tannich F, Tlili A, Pintard C, Chniguir A, Eto B, Dang PM, Souilem O, El-Benna J (2020) Activation of the phagocyte NADPH oxidase/NOX2 and myeloperoxidase in the mouse brain during pilocarpine-induced temporal lobe epilepsy and inhibition by ketamine. Inflammopharmacology 28(2):487–497. https://doi.org/10.1007/s10787-019-00655-9

    Article  CAS  PubMed  Google Scholar 

  55. Üllen A, Singewald E, Konya V, Fauler G, Reicher H, Nusshold C et al (2013) Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo. PLoS One 8:e64034. https://doi.org/10.1371/journal.pone.0064034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785

    CAS  PubMed  Google Scholar 

  57. Vavakova M, Durackova Z, Trebatick J (2015) Markers of oxidative stress and neuroprogression in depression disorder. Oxid Med Cell Longev 12:898393. https://doi.org/10.1155/2015/898393

    Article  Google Scholar 

  58. Olugbemide AS, Ben-Azu B, Bakre AG, Ajayi AM, Femi-Akinlosotu O, Umukoro S (2021) Naringenin improves depressive- and anxiety-like behaviors in mice exposed to repeated hypoxic stress through modulation of oxido-inflammatory mediators and NF-κB/BDNF expressions. Brain Res Bull 169:214–227

  59. Li Z, Li J, Zhao W, Li Y (2020) Potential antiosteoporotic effect of Ginkgo biloba extract via regulation of SIRT1-NF-κB signaling pathway. J King Saud Univ-Sci 32(4):2513–2519

  60. Rafaiee R, Khastar H, Garmabi B, Taleb M, Norouzi P, Khaksari M (2021) Hydrogen sulfide protects hippocampal CA1 neurons against lead mediated neuronal damage via reduction oxidative stress in male rats. J Chem Neuroanat 112:101917

    CAS  PubMed  Google Scholar 

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Acknowledgements

Authors appreciate the technical assistant rendered during this study by Mr. Savior Inegbenehi and Mr. Martin U. Ukiwa of the Department of Biochemistry and Pharmacology, PAMO University Medical Sciences, Port Harcourt.

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Authors and Affiliations

  1. Neurophysiology Unit, Department of Physiology, PAMO University of Medical Sciences, Port-Harcourt, River State, Nigeria

    Olusegun G. Adebayo, Tolunigba A. Kolawole & Elizabeth B. Umoren

  2. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Benneth Ben-Azu

  3. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State, Nigeria

    Abayomi M. Ajayi

  4. Department of Biochemistry, Faculty of Basic Medical Sciences, University of Port Harcourt, Port Harcourt, River State, Nigeria

    Iheanyichukwu Wopara

  5. Department of Physiology, Bayelsa Medical University, Yenagoa, Bayelsa State, Nigeria

    Wadioni Aduema

  6. Department of Anatomy, PAMO University of Medical Sciences, Port-Harcourt, River State, Nigeria

    Ijeoma Onyeleonu

  7. Department of Community Medicine, Faculty of Clinical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Oloruntoba T. Ebo

  8. Department of Pharmacy, Faculty of Clinical Sciences, University of Port Harcourt, Port Harcourt, River State, Nigeria

    Doris N. Ajibo

  9. Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Enugu, Enugu State, Nigeria

    Ajirioghene E. Akpotu

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  1. Olusegun G. Adebayo
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  2. Benneth Ben-Azu
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  3. Abayomi M. Ajayi
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  8. Ijeoma Onyeleonu
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  9. Oloruntoba T. Ebo
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  11. Ajirioghene E. Akpotu
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Contributions

Olusegun G. Adebayo—designed, managed the laboratory experiment and wrote the first draft of the manuscript. Benneth Ben-Azu—contributed in the design of the experiment, managed the laboratory experiment and participated in the writing of the manuscript. Abayomi M. Ajayi—managed the statistical analysis and participated in the writing of the manuscript. Iheanyichukwu Wopara—managed the laboratory experiment and statistical analysis. Wadioni Aduema—managed the laboratory experiment and statistical analysis. Tolunigba A. Kolawole—provided the materials for the study and managed the laboratory experiment. Elizabeth B. Umoren—managed the laboratory experiment and methodology. Ijeoma Onyeleonu—managed the laboratory experiment and methodology. Oloruntoba T. Ebo—provided the materials for the study and managed the literature searches. Doris N. Ajibo—Provided the materials for the study and managed the literature searches. Ajirioghene E. Akpotu—managed the literature searches and methodology. All authors read and approved the submission of the manuscript.

The institution, PAMO University of Medical Sciences Animal Research Ethics Committee (PUMS-AREC) which agreed with the “Guide to the care and use of laboratory animals in research and teaching” as prescribed in NIH publications volume 25 No.28 revised in 1996 approved the use of animal for this study

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Correspondence to Olusegun G. Adebayo or Benneth Ben-Azu.

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Adebayo, O.G., Ben-Azu, B., Ajayi, A.M. et al. Gingko biloba abrogate lead-induced neurodegeneration in mice hippocampus: involvement of NF-κB expression, myeloperoxidase activity and pro-inflammatory mediators. Biol Trace Elem Res 200, 1736–1749 (2022). https://doi.org/10.1007/s12011-021-02790-3

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