Green Tea Polyphenols Protect Cochlear Hair Cells from Ototoxicity

by | Nov 25, 2020 | 2015, Ear, Nose and Throat, Polyphenols

Written by Angeline A. De Leon, Staff Writer. Researchers demonstrated that catechin epigallocatechin gallate (EGCG) could promote hearing-impaired recovery by suppressing the Notch signaling pathway.

green teaThe Notch signaling pathway is a cell signaling system in mammals associated with key cellular processes such as cell proliferation, cell differentiation, and cell death, and according to otological research, appears to play a role in the development of the cochlea 1. As transmembrane proteins, Notch receptors are involved in cell-to-cell communication 2 and contribute to the development of cochlear hair cells by regulating hair cell differentiation through their interactions with ligands 3. Newer work suggests that proliferation of hair cells is possible by inactivating the Notch signaling pathway 4, leading some researchers to experiment with suppressing Notch activity in order to promote hair cell regeneration in damaged cochleae 5. Recent research has also highlighted the valuable benefits of tea polyphenols, particularly the powerful antioxidant capacity of EGCG 6. EGCG boasts greater antioxidant activity than Vitamin C 7 and demonstrates the ability to reduce oxidative stress levels 8. The phytochemical has also been studied for its favorable role in viral infections 9 and osteoporosis 10. Given the potent antioxidant activity associated with EGCG 6, researchers at Shandong University hypothesized that EGCG might be able to protect cochlear hair cells from the ototoxic effects associated with certain medications 11 . In 2015, the beneficial role of EGCG in protecting cochlear hair cells was evaluated based on its effects on the Notch signaling pathway.

Cochlear tissues were isolated from the embryos of Atoh1 (involved in development and regeneration of cochlear hair cells) transgenic mice and cultured in vitro. Cochlear explant cultures were treated with 40 µg/ml gentamicin (antibiotic with ototoxic effects), 40 µg/ml gentamicin plus 40 µg/ml EGCG, or a control solution for 24 hours. Hair cells of cochlear tissues were quantified following treatment, and quantitative real-time polymerase chain reaction (RT-PCR) assay was carried out to determine the mRNA expression of four Notch pathway target genes (Hes1, Hes5, Hey1, and Hey5), as well as pathway ligands Delta1, Jag1, and Jag2. Western blotting analysis was also performed on mouse fibroblasts to assess the activity of gamma-secretase, a hypothesized target of EGCG, following treatment with L685458 (a known inhibitor of gamma-secretase).

Whereas cochlear hair cells treated with gentamicin were seen to exhibit marked signs of damage and a decrease in hair cell count by 80%, compared to controls, treatment with EGCG resulted in preserved structural integrity of hair cells and relative maintenance of hair cell count. RT-PCR assay revealed that although no significant changes in the protein expression of Notch ligands were associated with EGCG, treatment with gentamicin plus EGCG was linked to significant down-regulation of mRNA levels for Hes1, Hes5, Hey1, and Hey5, compared to treatment with gentamicin alone (p < 0.05 for all). Finally, researchers found evidence to suggest that EGCG produced an inhibitory effect on gamma-secretase activity, based on the observation that EGCG acted similarly to L685458 in suppressing proteolytic release of Notch intracellular domain (NICD), a key step in the activation of the Notch signaling pathway.

Findings from the present study shed light on the protective role of EGCG against ototoxic effects. A series of experiments carried out in cochlear explant cultures confirmed that treatment with EGCG effectively mitigated structural damage to cochlear hair cells caused by gentamicin and successfully prevented loss of hair cells. EGCG was also seen to efficiently inhibit the Notch signaling pathway by downregulating the expression of key target genes and also inactivating gamma-secretase to directly suppress Notch activity. Thus, through the mechanism proposed here, EGCG appears to offer valuable clinical potential to facilitate hearing-impaired recovery. Clinical testing should be forthcoming.

Source: Gu L, Yang J, Su S, et al. Green tea polyphenols protect cochlear hair cells from ototoxicity by inhibiting notch signaling. Neurochem Res. 2015; 40(6): 1211-9. DOI: 10.1007/s11064-015-1584-3.

© Springer Science+Business Media New York 2015

Posted November 25, 2020.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

References:

  1. Lanford PJ, Lan Y, Jiang R, et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet. 1999;21(3):289-292.
  2. Baron M. An overview of the Notch signalling pathway. Seminars in cell & developmental biology. 2003;14(2):113-119.
  3. Haddon C, Jiang YJ, Smithers L, Lewis J. Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant. Development (Cambridge, England). 1998;125(23):4637-4644.
  4. Groves AK. The challenge of hair cell regeneration. Experimental biology and medicine (Maywood, NJ). 2010;235(4):434-446.
  5. Mizutari K, Fujioka M, Hosoya M, et al. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron. 2013;77(1):58-69.
  6. Mukhtar H, Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr. 2000;71(6 Suppl):1698S-1702S; discussion 1703S-1694S.
  7. Shah A, Kurlandsky S. Green tea and bilberry extracts but not vitamin C protect retinal epithelial cells from oxidative damage. The FASEB Journal. 2007;21(5):A172-A172.
  8. Pietta P, Simonetti P, Gardana C, Brusamolino A, Morazzoni P, Bombardelli E. Relationship between rate and extent of catechin absorption and plasma antioxidant status. Biochemistry and molecular biology international. 1998;46(5):895-903.
  9. Xiao X, Yang ZQ, Shi LQ, Liu J, Chen W. [Antiviral effect of epigallocatechin gallate (EGCG) on influenza A virus]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2008;33(22):2678-2682.
  10. Jin P, Wu H, Xu G, Zheng L, Zhao J. Epigallocatechin-3-gallate (EGCG) as a pro-osteogenic agent to enhance osteogenic differentiation of mesenchymal stem cells from human bone marrow: an in vitro study. Cell and tissue research. 2014;356(2):381-390.
  11. Gu LT, Yang J, Su SZ, Liu WW, Shi ZG, Wang QR. Green Tea Polyphenols Protects Cochlear Hair Cells from Ototoxicity by Inhibiting Notch Signalling. Neurochem Res. 2015;40(6):1211-1219.