(−)-Epigallocatechin-3-gallate Protects Against Neuronal Cell Death and Improves Cerebral Function After Traumatic Brain Injury in Rats

Abstract

A major component of green tea, a widely consumed beverage, is (−)-epigallocatechin gallate (EGCG), which has strong antioxidant properties. Our previous study has indicated that free radical production following rat traumatic brain injury (TBI) induces neural degeneration. In this study, we investigated the effects of EGCG on cerebral function and morphology following TBI. Six-week-old male Wistar rats that had access to normal drinking water, or water containing 0.1% (w/v) EGCG ad libitum, received TBI with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3 and 7 days post-TBI, the number of 8-hydroxy-2′-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and the levels of malondialdehyde (MDA) around the damaged area after TBI, significantly decreased in the EGCG treatment group compared with the water group (P < 0.05). Most ssDNA-positive cells in the water group co-localized with neuronal cells. However, in the EGCG treatment group, few ssDNA-positive cells co-localized with neurons. In addition, there was a significant increase in the number of surviving neuronal cells and an improvement in cerebral dysfunction after TBI in the EGCG treatment group compared with the water group (P < 0.05). These results indicate that consumption of water containing EGCG pre- and post-TBI inhibits free radical–induced neuronal degeneration and apoptotic cell death around the damaged area, resulting in the improvement of cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Ates, O., Cayli, S., Altinoz, E., Gurses, I., Yucel, N., Sener, M., et al. (2007). Neuroprotection by resveratrol against traumatic brain injury in rats. Molecular and Cellular Biochemistry, 294, 137–144.

    PubMed  Article  CAS  Google Scholar 

  2. Buffo, A., Rolando, C., & Ceruti, S. (2010). Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential. Biochemical Pharmacology, 79, 77–89.

    PubMed  Article  CAS  Google Scholar 

  3. Chan, P. H., Fishman, R. A., Longar, S., Chen, S., & Yu, A. (1985). Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury. Progress in Brain Research, 63, 227–235.

    PubMed  Article  CAS  Google Scholar 

  4. Chirumamilla, S., Sun, D., Bullock, M. R., & Colello, R. J. (2002). Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. Journal of Neurotrauma, 19, 693–703.

    PubMed  Article  CAS  Google Scholar 

  5. Gage, F. H. (2000). Mammalian neural stem cells. Science, 287, 1433–1438.

    PubMed  Article  CAS  Google Scholar 

  6. Hall, E. D., & Braughler, J. M. (1989). Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radical Biology and Medicine, 6, 303–313.

    PubMed  Article  CAS  Google Scholar 

  7. Hong, J. T., Ryu, S. R., Kim, H. J., Lee, J. K., Lee, S. H., Kim, D. B., et al. (2000). Neuroprotective effect of green tea extract in experimental ischemia-reperfusion brain injury. Brain Research Bulletin, 53, 743–749.

    PubMed  Article  CAS  Google Scholar 

  8. Itoh, T., Imano, M., Nishida, S., Tsubaki, M., Hashimoto, S., Ito, A., et al. (2011). Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury. Journal of Neural Transm, 118, 1263–1272.

    Article  Google Scholar 

  9. Itoh, T., Satou, T., Hashimoto, S., & Ito, H. (2005). Isolation of neural stem cells from damaged rat cerebral cortex after TBI. Neuroreport, 16, 1687–1691.

    PubMed  Article  Google Scholar 

  10. Itoh, T., Satou, T., Hashimoto, S., & Ito, H. (2007). Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurological Research, 29, 734–742.

    PubMed  Article  CAS  Google Scholar 

  11. Itoh, T., Satou, T., Nishida, S., Tsubaki, M., Hashimoto, S., & Ito, H. (2009a). Improvement of cerebral function by anti-amyloid precursor protein antibody infusion after traumatic brain injury in rats. Molecular and Cellular Biochemistry, 324, 191–199.

    PubMed  Article  CAS  Google Scholar 

  12. Itoh, T., Satou, T., Nishida, S., Tsubaki, M., Hashimoto, S., & Ito, H. (2009b). The novel free radical scavenger, edaravone, increases neural stem cell number around the area of damage following rat traumatic brain injury. Neurotoxicity Research, 16, 378–389.

    PubMed  Article  CAS  Google Scholar 

  13. Itoh, T., Satou, T., Nishida, S., Tsubaki, M., Imano, M., Hashimoto, S., et al. (2010). Edaravone protects against apoptotic neuronal cell death and improves cerebral function after traumatic brain injury in rats. Neurochemical Research, 35, 348–355.

    PubMed  Article  CAS  Google Scholar 

  14. Jang, S., Jeong, H. S., Park, J. S., Kim, Y. S., Jin, C. Y., Seol, M. B., et al. (2010). Neuroprotective effects of (−)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. Brain Research, 1313, 25–33.

    PubMed  Article  CAS  Google Scholar 

  15. Kawamata, T., Katayama, Y., Hovda, D. A., Yoshino, A., & Becker, D. P. (1995). Lactate accumulation following concussive brain injury: The role of ionic fluxes induced by excitatory amino acids. Brain Research, 674, 196–204.

    PubMed  Article  CAS  Google Scholar 

  16. Kontos, H. A. (1985). George E. Brown memorial lecture. Oxygen radicals in cerebral vascular injury. Circulation Research, 57, 508–516.

    PubMed  CAS  Google Scholar 

  17. Lee, H., Bae, J. H., & Lee, S. R. (2004). Protective effect of green tea polyphenol EGCG against neuronal damage and brain edema after unilateral cerebral ischemia in gerbils. Journal of Neuroscience Research, 77, 892–900.

    PubMed  Article  CAS  Google Scholar 

  18. Lee, S. Y., Kim, C. Y., Lee, J. J., Jung, J. G., & Lee, S. R. (2003). Effects of delayed administration of (−)-epigallocatechin gallate, a green tea polyphenol on the changes in polyamine levels and neuronal damage after transient forebrain ischemia in gerbils. Brain Research Bulletin, 61, 399–406.

    PubMed  Article  CAS  Google Scholar 

  19. Lee, E. J., Lee, M. Y., Chen, H. Y., Hsu, Y. S., Wu, T. S., Chen, S. T., et al. (2005). Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. Journal of Pineal Research, 38, 42–52.

    PubMed  Article  CAS  Google Scholar 

  20. Loren, D. J., Seeram, N. P., Schulman, R. N., & Holtzman, D. M. (2005). Maternal dietary supplementation with pomegranate juice is neuroprotective in an animal model of neonatal hypoxic-ischemic brain injury. Pediatric Research, 57, 858–864.

    PubMed  Article  CAS  Google Scholar 

  21. McGraw, J., Hiebert, G. W., & Steeves, J. D. (2001). Modulating astrogliosis after neurotrauma. Journal of Neuroscience Research, 63, 109–115.

    PubMed  Article  CAS  Google Scholar 

  22. Park, J. W., Jang, Y. H., Kim, J. M., Lee, H., Park, W. K., Lim, M. B., et al. (2009). Green tea polyphenol (−)-epigallocatechin gallate reduces neuronal cell damage and up-regulation of MMP-9 activity in hippocampal CA1 and CA2 areas following transient global cerebral ischemia. Journal of Neuroscience Research, 87, 567–575.

    PubMed  Article  CAS  Google Scholar 

  23. Rice, A. C., Khaldi, A., Harvey, H. B., Salman, N. J., White, F., Fillmore, H., et al. (2003). Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Experimental Neurology, 183, 406–417.

    PubMed  Article  CAS  Google Scholar 

  24. Sakurai, M., Nagata, T., Abe, K., Horinouchi, T., Itoyama, Y., & Tabayashi, K. (2003). Oxidative damage and reduction of redox factor-1 expression after transient spinal cord ischemia in rabbits. Journal of Vascular Surgery, 37, 446–452.

    PubMed  Article  Google Scholar 

  25. Sugawara, T., Noshita, N., Lewen, A., Gasche, Y., Ferrand-Drake, M., Fujimura, M., et al. (2002). Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. Journal of Neuroscience, 22, 209–217.

    PubMed  CAS  Google Scholar 

  26. Wang, X., Karlsson, J. O., Zhu, C., Bahr, B. A., Hagberg, H., & Blomgren, K. (2001). Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia. Biology of the Neonate, 79, 172–179.

    PubMed  Article  CAS  Google Scholar 

  27. Weinreb, O., Amit, T., Mandel, S., & Youdim, M. B. (2009). Neuroprotective molecular mechanisms of (−)-epigallocatechin-3-gallate: A reflective outcome of its antioxidant, iron chelating and neuritogenic properties. Genes & Nutrition, 4, 283–296.

    Article  CAS  Google Scholar 

  28. Weissman, L., de Souza-Pinto, N. C., Stevnsner, T., & Bohr, V. A. (2007). DNA repair, mitochondria, and neurodegeneration. Neuroscience, 145, 1318–1329.

    PubMed  Article  CAS  Google Scholar 

  29. Won, M. H., Kang, T., Park, S., Jeon, G., Kim, Y., Seo, J. H., et al. (2001). The alterations of N-Methyl-d-aspartate receptor expressions and oxidative DNA damage in the CA1 area at the early time after ischemia-reperfusion insult. Neuroscience Letters, 301, 139–142.

    PubMed  Article  CAS  Google Scholar 

  30. Xiong, Y., Gu, Q., Peterson, P. L., Muizelaar, J. P., & Lee, C. P. (1997). Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. Journal of Neurotrauma, 14, 23–34.

    PubMed  Article  CAS  Google Scholar 

  31. Xiong, Y., Mahmood, A., Lu, D., Qu, C., Kazmi, H., Goussev, A., et al. (2008). Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Research, 1230, 247–257.

    PubMed  Article  CAS  Google Scholar 

  32. Yu, J., Jia, Y., Guo, Y., Chang, G., Duan, W., Sun, M., et al. (2010). Epigallocatechin-3-gallate protects motor neurons and regulates glutamate level. FEBS Letter, 584, 2921–2925.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Grant-in-Aid for Scientific Research (21500803). The authors thank Mari Yachi for technical assistance.

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Tatsuki Itoh.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Itoh, T., Imano, M., Nishida, S. et al. (−)-Epigallocatechin-3-gallate Protects Against Neuronal Cell Death and Improves Cerebral Function After Traumatic Brain Injury in Rats. Neuromol Med 13, 300–309 (2011). https://doi.org/10.1007/s12017-011-8162-x

Download citation

Keywords

  • Epigallocatechin
  • Traumatic brain injury
  • Neuroprotection
  • Apoptosis
  • Oxidative stress