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https://doi.org/10.53941/jmnp.2025.100010
Farag, M. M., Wagdy, M. A., Ahmed, H. E., & Kazem, A. H. The Potential Protective Effect of the Standardized Ginkgo biloba Leaves Extract EGb761 against Contrast-Induced Acute Kidney Toxicity in Rats via Mitigating Renal Tissue Redox Imbalance, Inflammation, Cell Apoptosis and Mitochondrial Damage. Journal of Medicinal Natural Products. 2025, 2(2), 100010. doi: https://doi.org/10.53941/jmnp.2025.100010
Volume 2, Issue 2, 2025
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This work is licensed under a Creative Commons Attribution 4.0 International License.

Article

The Potential Protective Effect of the Standardized Ginkgo biloba Leaves Extract EGb761 against Contrast-Induced Acute Kidney Toxicity in Rats via Mitigating Renal Tissue Redox Imbalance, Inflammation, Cell Apoptosis and Mitochondrial Damage

Mahmoud M. Farag 1,*, Mariam A. Wagdy 1, Heba E. Ahmed 1, and Amani H. Kazem 2

1 Departments of Pharmacology, Medical Research Institute, Alexandria University, Alexandria 21561 Egypt

2 Departments of Pathology, Medical Research Institute, Alexandria University, Alexandria 21561 Egypt

* Correspondence: mahmoudfarag2012@hotmail.com; Tel.: +20-1006632014

Received: 25 March 2025; Revised: 13 April 2025; Accepted: 14 April 2025; Published: 6 May 2025

Abstract: In clinical medical practice, the applications of diagnostic and interventional procedures requiring iodinated contrast media (CM) administration have recently markedly increased. However, the intrinsic CM toxicity may lead to contrast-induced acute kidney injury (CI-AKI), particularly in patients with renal disease or diabetes. As successful therapy of CI-AKI is rather limited, effective strategies to prevent CI-AKI have become an insistent demand. The aim of this study was to evaluate the potential protective effects of the standardized extract of Ginkgo biloba leaves EGb761 against the pathophysiology of CI-AKI in a rat model. In this study, CI-AKI in rats was evaluated histopathologically and biochemically by measuring serum biomarkers of kidney function and tissue markers of oxidative stress, inflammation, tubular cell apoptosis and mitochondrial injury. Our results showed that CM administration led to several kidney morphological changes with alterations in serum and renal tissue parameters indicative of acute renal toxicity. These changes were moved to normality upon EGb761 treatment before CM exposure via integrated suppression of CM-induced renal tissue redox imbalance, inflammatory response, cell apoptosis activation and tubular cell mitochondrial damage. These findings demonstrated the nephroprotective effectiveness of EGb761 in alleviating CI-AKI pathophysiology through multiple effects. In conclusion, our study suggests a new therapeutic strategy for attenuating CI-AKI via administering EGb761 before CM use and may serve as an experimental basis for further studies to elucidate the promising clinical impact of EGb761 as a nephroprotective agent in patients at the risk of developing CI-AKI.

Keywords:

EGb761 CI-AKI oxidative stress inflammation apoptosis mitochondrial damage

References

  1. Perazella, M.A. Renal vulnerability to drug toxicity. Clin. J. Am. Soc. Nephrol. 2009, 4, 1275–1283. doi: 10.2215/CJN.02050309
  2. Alshowiman, S.S.; Sahrah, A.; Alswailem, A.K.; et al. Iodinated contrast media. World J. Adv. Res. Rev. 2021, 9, 156–167. doi: 10.30574/wjarr.2021.9.1.0508
  3. Azzalini, L.; Kalra, S. Contrast-induced acute kidney injury:definitions, epidemiology and implications. Int. Cardiol. Clin. 2020, 9, 299–309. doi: 10.1016/j.iccl.2020.02.001
  4. Pisani, A.; Riccio, E.; Andreucci, M.; Faga, T.; Ashour, M.; Di nuzzi, A.; et al. Role of reactive oxygen species in pathogenesis of radiocontrast-induced nephropathy. Biomed Res. Int. 2013, 2013, 868321. doi: 10.1155/2013/868321
  5. Quintavalle, C.; Brenca, M.; De Micco, F.; et al. In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis. Cell Death Dis. 2011, 2, e155. doi: 10.1038/cddis.2011.38
  6. Heyman, S.N.; Rosen, S.; Rosenberger, C. Renal parenchymal hypoxia. hypoxia adaptation and the pathogenesis of radiocontrast nephropathy. Clin. J. Am. Soc. Nephrol. 2008, 3, 288–296. doi: 10.2215/CJN.02600607
  7. Agmon, Y.; Peleg, H.; Greenfeld, Z.; et al. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J. Clin. Investig. 1994, 94, 1069–1075. doi: 10.1172/JCI117421
  8. Lee, H.T.; Jan, M.; Bae, S.C.; et al. A1 adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo. Am. J. Physiol.-Renal Physiol. 2006, 290, F1367–F1375. doi: 10.1152/ajprenal.00347.2005
  9. Cho, E.; Ko, G.-J. The pathophysiology and the management of radiocontrast-induced nephropathy. Diagnostics 2022, 12, 180. doi: 10.3390/diagnostics12010180
  10. Isaka, Y.; Hayashi, H.; Aonuma, K.; et al. Guidelines on the use of iodinated contrast media in patients with kidney disease 2018. Jpn. J. Radiol. 2020, 38, 3–46. doi: 10.1007/s11604-019-00850-2
  11. Su, X.; Xie, X.; Liu, L.; et al. Comparative effectiveness of 12 treatment strategies for preventing contrast-induced acute kidney injury: A systematic review and Bayesian network meta-analysis. Am. J. Kidney Dis. 2017, 69, 69–77. doi: 10.1053/j.ajkd.2016.07.033
  12. Topaloğlu, U.S.; Sipahioğlu, M.H.; Güntürk, İ.; et al. Effects of thymoquinone in prevention of experimental contrast-induced nephropathy in rats. Iran. J. Basic. Med. Sci. 2019, 22, 1432–1439.
  13. Spångberg-Viklund, B.; Berglund, J.; Nikonoff, T.; et al. Does prophylactic treatment with felodipine, a calcium antagonist, prevent low-osmolar contrast-induced renal dysfunction in hydrated diabetic and nondiabetic patients with normal or moderately reduced renal function? Scand. J. Urol. Nephrol. 1996, 30, 63–68. doi: 10.3109/00365599609182351
  14. Biernacka, P.; Adamska, I.; Felisiak, K. The potential of Ginkgo biloba as a source of biologically active compounds—A review of the recent literature and patents. Molecules. 2023, 28, 3993. doi: 10.3390/molecules28103993
  15. Mahadevan, S.; Park, Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: Chemistry, efficacy, safety, and uses. J. Food Sci. 2008, 73, R14–R19. doi: 10.1111/j.1750-3841.2007.00597.x
  16. Mahady, G. B. Ginkgo biloba for the prevention and treatment of cardiovascular disease: A review of the literature. J. Cardiovasc. Nurs. 2002, 16, 21–32. doi: 10.1097/00005082-200207000-00004
  17. Yang, G.; Wang, Y.; Sun, J.; et al. Ginkgo biloba for mild cognitive impairment and Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. Curr. Top. Med. Chem. 2016, 16, 520–528. doi: 10.2174/1568026615666150813143520
  18. Tabassum, N.E.; Das, R.; Lami, M.S.; et al. Ginkgo biloba: A treasure of functional phytochemicals with multimedicinal applications. Evid. Based Complement. Alternat. Med. 2022, 2022, 8288818. doi: 10.1155/2022/8288818
  19. Abd-Ellah, M.F.; Mariee, A.D. Ginkgo biloba leaf extract (EGb 761) diminishes adriamycin-induced hyperlipidemic nephrotoxicity in rats: Association with nitric oxide production. Biotechnol. Appl. Biochem. 2007, 46, 35–40. doi: 10.1042/BA20060085
  20. Song, J.; Liu, D.; Feng, L.; et al. Protective effect of extract of Ginkgo biloba against cisplatin-induced nephrotoxicity. Evid. Based Complement. Alternat. Med. 2013, 2013, 846126. doi: 10.1155/2013/846126
  21. Sherif, I.O.; Al-Mutabagani, L.A.; Sarhan, O.M. Ginkgo biloba extract attenuates methotrexate-induced testicular injury in rats: Cross-talk between oxidative stress, inflammation, apoptosis and miRNA-29a expression. Integr. Cancer Ther. 2020, 19, 1534735420969814. doi: 10.1177/1534735420969814
  22. Draper, H.H.; Hadley, M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990, 186, 421–431. doi: 10.1016/0076-6879(90)86135-I
  23. Griffith, O.W. Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal. Biochem. 1980, 106, 207–212. doi: 10.1016/0003-2697(80)90139-6
  24. Marklund, S.; Marklund, G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem. 1974, 47, 469–474. doi: 10.1111/j.1432-1033.1974.tb03714.x
  25. Ekstrand, M.I.; Falkenberg, M.; Rantanen, A.; et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 2004, 13, 935–944. doi: 10.1093/hmg/ddh109
  26. Oriquat, G.A.; Ali, M.A.; Mahmoud, S.A.; et al. Improving hepatic mitochondrial biogenesis as a postulated mechanism for the antidiabetic effect of Spirulina platensis in comparison with metformin. Appl. Physiol. Nut. Metab. 2019, 44, 357–364. doi: 10.1139/apnm-2018-0354
  27. Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; et al. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951, 193, 265–275. doi: 10.1016/S0021-9258(19)52451-6
  28. Ghasemi, A.; Zahediasl, S. Normality tests for statistical analysis: A guide for non- statisticians. Int. J. Endocrinol. Metab. 2012, 10, 486–489. doi: 10.5812/ijem.3505
  29. Nickolas, T.L.; Barasch, J.; Devarajan, P. Biomarkers in acute and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 2008, 17, 127–132. doi: 10.1097/MNH.0b013e3282f4e525
  30. Salazar, J.H. Overview of urea and creatinine. Lab. Med. 2014, 45, e19–e20. doi: 10.1309/LM920SBNZPJRJGUT
  31. Bolignano, D.; Donato, V.; Coppolino, G.; et al. Neutrophil gelatinase–associated lipocalin (NGAL) as a marker of kidney damage. Am. J. Kidney Dis. 2008, 52, 595–605. doi: 10.1053/j.ajkd.2008.01.020
  32. Devarajan, P. Neutrophil gelatinase-associated lipocalin: A troponin-like biomarker for human acute kidney injury. Nephrology. 2010, 15, 419–428. doi: 10.1111/j.1440-1797.2010.01317.x
  33. Andreucci, M.; Faga, T.; Riccio, E.; et al. The potential use of biomarkers in predicting contrast-induced acute kidney injury. Int. J. Nephrol. Renovasc. Dis. 2016, 9, 205–221. doi: 10.2147/IJNRD.S105124
  34. Heyman, S.N.; Rosen, S.; Khamaisi, M.; et al. Reactive oxygen species and the pathogenesis of radiocontrast-induced nephropathy. Investig. Radiol. 2010, 45, 188–195. doi: 10.1097/RLI.0b013e3181d2eed8
  35. Kusirisin, P.; Chattipakorn, S.C.; Chattipakorn, N. Contrast-induced nephropathy and oxidative stress: Mechanistic insights for better interventional approaches. J. Transl. Med. 2020, 18, 400. doi: 10.1186/s12967-020-02574-8
  36. Mittal, M.; Siddiqui, M.R.; Tran, K.; et al. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 2014, 20, 1126–1167. doi: 10.1089/ars.2012.5149
  37. Pello, R.; Martín, M.A.; Carelli, V.; et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum. Mol. Genet. 2008, 17, 4001–4011. doi: 10.1093/hmg/ddn303
  38. Vakifahmetoglu-Norberg, H.; Ouchida, A.T.; Norberg, E. The role of mitochondria in metabolism and cell death. Biochem. Biophys. Res. Commun. 2017, 482, 426–431. doi: 10.1016/j.bbrc.2016.11.088
  39. Anderson, S.; Bankier, A.T.; Barrell, B.G.; et al. Sequence and organization of the human mitochondrial genome. Nature 1981, 290, 457–465. doi: 10.1038/290457a0
  40. Castellani, C.A.; Longchamps, R.J.; Sun, J.; et al. Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease. Mitochondrion 2020, 53, 214–223. doi: 10.1016/j.mito.2020.06.004
  41. Jin, L.; Yu, B.; Armando, I.; et al. Mitochondrial DNA-mediated inflammation in acute kidney injury and chronic kidney disease. Oxidative Med. Cell. Longev. 2021, 2021, 9985603. doi: 10.1155/2021/9985603
  42. Servais, H.; Ortiz, A.; Devuyst, O.; et al. Renal cell apoptosis induced by nephrotoxic drugs: Cellular and molecular mechanisms and potential approaches to modulation. Apoptosis 2008, 13, 11–32. doi: 10.1007/s10495-007-0151-z
  43. Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta (BBA)-Mol. Cell Res. 2016, 1863, 2977–2992.
  44. Bock, F.J.; Tait, S.W.G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Molec. Cell Biol. 2020, 21, 85–100. doi: 10.1038/s41580-019-0173-8
  45. Subramaniam, R.M.; Suarez-Cuervo, C.; Wilson, R.F.; et al. Effectiveness of prevention strategies for contrast-induced nephropathy: A systematic review and meta-analysis. Ann. Intern. Med. 2016, 164, 406–416. doi: 10.7326/M15-1456
  46. Welz, A.N.; Emberger-Klein, A.; Menrad, K. Why people use herbal medicine: Insights from a focus-group study in Germany. BMC Complement. Alternat. Med. 2018, 18, 92. doi: 10.1186/s12906-018-2160-6
  47. Tao, Z.; Jin, W.; Ao, M.; et al. Evaluation of the anti-inflammatory properties of the active constituentsin Ginkgo biloba for the treatment of pulmonary diseases. Food Funct. 2019, 10, 2209–2220. doi: 10.1039/C8FO02506A
  48. Grant, C.M. Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions. Mol. Microbiol. 2001, 39, 533–541. doi: 10.1046/j.1365-2958.2001.02283.x
  49. Fridovich, I. Superoxide anion radical (O2), superoxide dismutase, and related matters. J. Biolog. Chem. 1997, 272, 18515–18517. doi: 10.1074/jbc.272.30.18515
  50. Song, W.; Guan, H.J.; Zhu, X.Z.; et al. Protective effect of bilobalide against nitric oxide-induced neurotoxicityin PC12 cells. Acta Pharmacol. Sin. 2000, 21, 415–420.
  51. He, X.; Li, L.; Tan, H.; et al. Atorvastatin attenuates contrast-induced nephropathy by modulating inflammatory responses through the regulation of JNK/p38/Hsp27 expression. J. Pharmacol. Sci. 2016, 131, 18–27. doi: 10.1016/j.jphs.2016.03.006
  52. Farag, M.M.; Khalifa, A.A.; Elhadidy, W.F.; et al. Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulations of oxidative stress, inflammation, apoptosis, autophagy, and fibrosis. Naunyn Schiedeberg′s Arch. Pharmacol. 2021, 394, 1787–1801. doi: 10.1007/s00210-021-02087-1
  53. Lee, C.-Y.; Yang, J.-J.; Lee, S.-S.; et al. Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin-induced acute lung injury via a JNK-and Akt-dependent NFκB pathway. J. Agric. Food Chem. 2014, 62, 6337–6344. doi: 10.1021/jf501913b
  54. Gargouri, B.; Carstensen, J.; Bhatia, H.S.; et al. Anti-neuroinflammatory effects of Ginkgo biloba extract EGb761 in LPS-activated primary microglial cells. Phytomedicine 2018, 44, 45–55. doi: 10.1016/j.phymed.2018.04.009
  55. Yeh, Y.C.; Liu, T.J.; Wang, L.C.; et al. A standardized extract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and p53-mediated mitochondrial apoptosis in rat testes. Br. J. Pharmacol. 2009, 156, 48–61. doi: 10.1111/j.1476-5381.2008.00042.x
  56. Wu, C.; Zhao, X.; Zhang, X.; et al. Effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and related gene expression. Genet. Mol. Res. 2015, 14, 6387–6394. doi: 10.4238/2015.June.11.14
  57. Mosadegh, M.; Hasanzadeh, S.; Razi, M. Nicotine-induced damages in testicular tissue of rats; evidences for bcl-2, p53 and caspase-3 expression. Iran. J. Basic. Med. Sci. 2017, 20, 199–208.
  58. Bhargava, P.; Schnellmann, R.G. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 2017, 13, 629–646. doi: 10.1038/nrneph.2017.107
  59. Graziewicz, M.A.; Day, B.J.; Copeland, W.C. The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res. 2002, 30, 2817–2824. doi: 10.1093/nar/gkf392
  60. Baliutyte, G.; Trumbeckaite, S.; Baniene, R.; et al. Effects of standardized extract of Ginkgo biloba leaves EGb761 on mitochondrial functions: Mechanism (s) of action and dependence on the source of mitochondria and respiratory substrate. J. Bioenerg. Biomemb. 2014, 46, 493–501. doi: 10.1007/s10863-014-9590-8
  61. Dorta, D.J.; Pigoso, A.A.; Mingatto, F.E.; et al. Antioxidant activity of flavonoids in isolated mitochondria. Phytother. Res. 2008, 22, 1213–1218. doi: 10.1002/ptr.2441