Advertisement

Ginkgo biloba, DNA Damage and DNA Repair: Overview

  • Daniela Oliveira
  • Bjorn Johansson
  • Rui OliveiraEmail author
Reference work entry

Abstract

Despite the ancient use in Chinese popular medicine and, more recently, in western modern medicine in many European countries, the biological effects of extracts of G. biloba (GBE) are still not clearly known. In modern medicine GBE has been used for tinnitus, to reverse memory loss, for dementia, and Alzheimer’s and Parkinson’s diseases in elderly people. Besides reports on improvement of blood circulation in the brain, there are a number of studies pointing to complex cellular effects, involving signal transduction pathways and epigenetic modifications. Evidence are presented from recent reports concerning genotoxic and antigenotoxic properties and the corresponding mechanisms underlying such activities, mostly regarding the prooxidant and antioxidant activities of the extract. However, several examples of direct interaction of the extract and its components with specific proteins are provided, especially for DNA damage repair, contributing for antigenotoxicity. Evidence of epigenetic effects of GBE are also presented from approaches involving transcriptomics, detection of activity of histone deacetylases, and screening of plant extracts with cell-based systems for detection of posttranslational modifications. The modulation of chromatin-remodeling enzymes by GBE and their interaction with proteins involved in DNA damage repair, apoptosis, and signal transduction are discussed in the context of neurodegeneration.

Keywords

Ginkgo biloba Antioxidant Antigenotoxicity Genotoxicity Flavonoids DNA repair DNA damage Epigenetics Neuroprotection Alzheimer’s disease EGb 761 

List of Abbreviations

AD

Alzheimer’s disease

BER

Base excision repair

DSBs

Double-strand breaks

EGb 761

Standardized leaf extract of Ginkgo biloba

GBE

Ginkgo biloba extract

HDAC

Histone deacetylase

MAPK

Mitogen-activated protein kinases

NER

Nucleotide excision repair

ROS

Reactive oxygen species

SUMO

Small ubiquitin-like modifier

Topo II

Topoisomerase II

References

  1. Abdel-Wahab BA, Abd El-Aziz SM (2012) Ginkgo biloba protects against intermittent hypoxia-induced memory deficits and hippocampal DNA damage in rats. Phytomedicine 19:444–450CrossRefGoogle Scholar
  2. Alam SS, Hassan NS, Raafat BM (2013) Evaluation of oxidatively generated damage to DNA and proteins in rat liver induced by exposure to technetium radioisotope 99m and protective role of Angelica archangelica and Ginkgo biloba. WASJ 2:7–17Google Scholar
  3. Ayissi VBO, Ebrahimi A, Schluesenner H (2014) Epigenetic effects of natural polyphenols: a focus on SIRT1-mediated mechanisms. Mol Nutr Food Res 58:22–32CrossRefGoogle Scholar
  4. Bahri GG, Lamuki MS, Rezae-Raad MS (2014) Anti-proliferative effects of alcoholic and aqueous extract of Ginkgo biloba green leaves on MCF-7 cell line. IJMPR 2:8–11Google Scholar
  5. Baron-Ruppert G, Luepke N-P (2001) Evidence for toxic effects of alkylphenols from Ginkgo biloba in the hen’s egg test (HET). Phytomedicine 8:133–138CrossRefGoogle Scholar
  6. Berger A, Venturelli S, Kallnischkies M et al (2013) Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases. J Nutr Biochem 24:977–985CrossRefGoogle Scholar
  7. Bidon C, Lachuer J, Molgo J et al (2009) The extract of Ginkgo biloba EGb 761 reactivates a juvenile profile in the skeletal muscle of sarcopenic rats by transcriptional reprogramming. PLoS One 4:e7998CrossRefGoogle Scholar
  8. Boeing S, Williamson L, Encheva V et al (2016) Multiomic analysis of the UV-induced DNA damage response. Cell Rep 15:1597–1610CrossRefGoogle Scholar
  9. Boghdady NAE (2013) Antioxidant and antiapoptotic effects of proanthocyanidin and ginkgo biloba extract against doxorubicin-induced cardiac injury in rats. Cell Biochem Funct 31:344–351CrossRefGoogle Scholar
  10. Brochier C, Dennis G, Rivieccio MA et al (2013) Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci 33:8621–8632CrossRefGoogle Scholar
  11. Busch C, Burkard M, Leischner C et al (2015) Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clin Epigenetics 7:64CrossRefGoogle Scholar
  12. Carrero I, Gonzalo MR, Martin B et al (2012) Oligomers of beta-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Exp Neurol 236:215–227CrossRefGoogle Scholar
  13. Çavuşoğlu K, Yapar K, Oruç E et al (2011) Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice. J Med Food 14:1263–1272CrossRefGoogle Scholar
  14. Choudhary C, Kumar C, Gnad F et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840CrossRefGoogle Scholar
  15. Dardano A, Ballardin M, Ferdeghini M et al (2007) Anticlastogenic effect of Ginkgo biloba extract in graves’ disease patients receiving radioiodine therapy. J Clin Endocrinol Metab 92:4286–4289CrossRefGoogle Scholar
  16. Dorval V, Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and α-synuclein. J Biol Chem 281:9919–9924CrossRefGoogle Scholar
  17. El Mesallamy HO, Metwally NS, Soliman MS et al (2011) The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats. Cancer Cell Int 11:38CrossRefGoogle Scholar
  18. Fang L, Neutzner A, Turtschi S et al (2015) The effect of Ginkgo biloba and Nifedipine on DNA breaks in circulating leukocytes of glaucoma patients. Expert Rev Ophthalmol 10:313–318CrossRefGoogle Scholar
  19. Fukuda I, Ito A, Hirai G et al (2009) Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol 16:133–140CrossRefGoogle Scholar
  20. Govindarajan N, Rao P, Burkhardt S et al (2013) Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med 5:52–63CrossRefGoogle Scholar
  21. He J, Lin J, Li J et al (2009) Dual effects of Ginkgo biloba leaf extract on human red blood cells. Basic Clin Pharmacol Toxicol 104:138–144Google Scholar
  22. He Y-T, Xing S-S, Gao L et al (2014) Ginkgo biloba attenuates oxidative DNA damage of human umbilical vein endothelial cells induced by intermittent high glucose. Pharmazie 69:203–207PubMedGoogle Scholar
  23. Jiang W, Qiu W, Wang Y et al (2011) Ginkgo may prevent genetic-associated ovarian cancer risk: multiple biomarkers and anticancer pathways induced by ginkgolide B in BRCA1-mutant ovarian epithelial cells. Eur J Cancer Prev 20:508–517CrossRefGoogle Scholar
  24. Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382CrossRefGoogle Scholar
  25. Kaur N, Dhiman M, Perez-Polo JR et al (2015) Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Aβ25–35-induced neurotoxicity in human neuroblastoma cells. J Neurosci Res 93:938–947CrossRefGoogle Scholar
  26. Križková L, Chovanová Z, Ďuračková Z et al (2008) Antimutagenic in vitro activity of plant polyphenols: Pycnogenol® and Ginkgo biloba extract (EGb 761). Phytother Res 22:384–388CrossRefGoogle Scholar
  27. Kukucka J, Wyllie T, Read J et al (2013) Human neuronal cells: epigenetic aspects. Biomol Concepts 4:319–333CrossRefGoogle Scholar
  28. Kwok JBJ (2010) Role of epigenetics in Alzheimer’s and Parkinson’s disease. Epigenomics 2:671–682CrossRefGoogle Scholar
  29. Lee L, Dale E, Staniszewski A et al (2014) Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer’s disease. Sci Report 4:7190CrossRefGoogle Scholar
  30. Lin H, Guo X, Zhang S et al (2014) Mechanistic evaluation of Ginkgo biloba leaf extract-induced genotoxicity in L5178Y cells. Toxicol Sci 139:338–349CrossRefGoogle Scholar
  31. Liu T-J, Yeh Y-C, Ting C-T et al (2008) Ginkgo biloba extract 761 reduces doxorubicin-induced apoptotic damage in rat hearts and neonatal cardiomyocytes. Cardiovasc Res 80:227–235CrossRefGoogle Scholar
  32. Liu W-B, Ao L, Zhou Z-Y et al (2010) CpG island hypermethylation of multiple tumor suppressor genes associated with loss of their protein expression during rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. Biochem Biophys Res Commun 402:507–514CrossRefGoogle Scholar
  33. Longpré F, Garneau P, Christen Y et al (2006) Protection by EGb 761 against β-amyloid-induced neurotoxicity: involvement of NF-κB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation. Free Radic Biol Med 41:1781–1794CrossRefGoogle Scholar
  34. Marques F, Azevedo F, Johansson B et al (2011) Stimulation of DNA repair in Saccharomyces cerevisiae by Ginkgo biloba leaf extract. Food Chem Toxicol 49:1361–1366CrossRefGoogle Scholar
  35. Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133–138CrossRefGoogle Scholar
  36. Min K, Ebeler SE (2009) Quercetin inhibits hydrogen peroxide-induced DNA damage and enhances DNA repair in Caco-2 cells. Food Chem Toxicol 47:2716–2722CrossRefGoogle Scholar
  37. Osman NMS, Amer AS, Abdelwahab S (2016) Effects of Ginkgo biloba leaf extract on the neurogenesis of the hippocampal dentate gyrus in the elderly mice. Anat Sci Int 91:280–289CrossRefGoogle Scholar
  38. Poleshko A, Kossenkov AV, Shalginskikh N et al (2014) Human factors and pathways essential for mediating epigenetic gene silencing. Epigenetics 9:1280–1289CrossRefGoogle Scholar
  39. Priyadarsini RV, Vinothini G, Murugan RS et al (2011) The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutr Cancer 63:218–226CrossRefGoogle Scholar
  40. Ribeiro ML, Moreira LM, Arçari DP et al (2016) Protective effects of chronic treatment with a standardized extract of Ginkgo biloba L. in the prefrontal cortex and dorsal hippocampus of middle-aged rats. Behav Brain Res 313:144–150CrossRefGoogle Scholar
  41. Rivieccio MA, Brochier C, Willis DE et al (2009) HDAC6 is a target for protection and regeneration following injury in the nervous system. PNAS 106:19599–19604CrossRefGoogle Scholar
  42. Sadikovic B, Al-Romaih K, Squire JA et al (2008) Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genomics 9:394–408CrossRefGoogle Scholar
  43. Schindowski K, Leutner S, Kressmann S et al (2001) Age-related increase of oxidative stress-induced apoptosis in mice prevention by Ginkgo biloba extract (EGb761). J Neural Transm 108:969–978CrossRefGoogle Scholar
  44. Shi C, Liu J, Wu F et al (2010) Ginkgo biloba extract in Alzheimer’s disease: from action mechanisms to medical practice. Int J Mol Sci 11:107–123CrossRefGoogle Scholar
  45. Stindt MH, Carter SA, Vigneron AM et al (2011) MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity. Cell Cycle 10:3176–3188CrossRefGoogle Scholar
  46. Tramutola A, Pupo G, Di Domenico F et al (2016) Activation of p53 in Down syndrome and in the Ts65Dn mouse brain is associated with a pro-apoptotic phenotype. J Alzheimers Dis 52:359–371CrossRefGoogle Scholar
  47. Ude C, Schubert-Zsilavecz M, Wurglics M (2013) Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet 52:727–749CrossRefGoogle Scholar
  48. Vargas JE, Filippi-Chiela EC, Suhre T et al (2014) Inhibition of HDAC increases the senescence induced by natural polyphenols in glioma cells. Biochem Cell Biol 92:297–304CrossRefGoogle Scholar
  49. Vaziri H, Dessain SK, Eaton EN et al (2001) hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell 107:149–159CrossRefGoogle Scholar
  50. Vilar JB, Leite KR, Chen LC (2009) Antimutagenicity protection of Ginkgo biloba extract (Egb 761) against mitomycin C and cyclophosphamide in mouse bone marrow. Genet Mol Res 8:328–333CrossRefGoogle Scholar
  51. World Health Organization (1999) WHO monographs on selected medicinal plants, vol 1. World Health Organization, Geneva, pp 154–167Google Scholar
  52. Wu L-Y, Lu H-F, Chou Y-C et al (2015) Kaempferol induces DNA damage and inhibits DNA repair associated protein expressions in human promyelocytic leukemia HL-60 cells. Am J Chin Med 43:365–382CrossRefGoogle Scholar
  53. Yang SH, Sharrocks AD (2004) SUMO promotes HDAC-mediated transcriptional repression. Mol Cell 13:611–617CrossRefGoogle Scholar
  54. Yeung F, Hoberg JE, Ramsey CS et al (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380CrossRefGoogle Scholar
  55. Zhang Z, Peng D, Zhu H et al (2012) Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats. Brain Res Bull 87:193–198CrossRefGoogle Scholar
  56. Zhang Z, Chen S, Mei H et al (2015) Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells. Sci Report 5:14633CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Daniela Oliveira
    • 1
  • Bjorn Johansson
    • 2
  • Rui Oliveira
    • 1
    • 3
    Email author
  1. 1.Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Department of BiologyUniversity of MinhoBragaPortugal
  2. 2.Centre of Molecular and Environmental Biology (CBMA), Department of BiologyUniversity of MinhoBragaPortugal
  3. 3.Centre of Biological Engineering (CEB), Department of BiologyUniversity of MinhoBragaPortugal

Personalised recommendations