ROS include molecules such as superoxide, H2O2, the hydroxyl radical, singlet oxygen, and hypochloric acid, and play many important physiological roles. They aid in the destruction of microbes and tumor cells, but may also alter and damage several components of normal cells, including membrane proteins/lipids and DNA, and may result in cancer induction. Many ROS effects depend upon the levels of the free radicals. EGCG, like other "antioxidants," decreases ROS levels at low concentrations and increases them at high concentrations .
Superoxide functions as a key ROS. It is converted into H2O2 by superoxide dis-mutase within cells. H2O2 is degraded into water and O2 by catalase. EGCG scavenges superoxide and elevates the activity of both protective superoxide dismutase and catalase in neurons [23, 50]. All phagocytic cells, including brain microglia, produce and release ROS. These cells also contain protective enzymes to inactivate the free radicals, including glutathione peroxidase (GPx), which is expressed at higher levels in microglia than neurons. During aging in mice, activity levels of
GPx, but not catalase, declined. When mice ingested green tea catechins, however, their GPx activity was similar to that of much younger animals . Amounts of GPx protein itself were not significantly decreased by aging or affected by tea consumption. Levels of NO and nNOS do, however, increase in aged mice, and this RNS has been found to inhibit GPx activity. As discussed below, EGCG blocks NO generation.
Much of the pathology in the CNS disorders described earlier in this chapter involves ROS. At low concentrations, EGCG decreases ROS production . It does so in neurons even in the presence of buthionine sulfoximine, an inhibitor of glu-tathione synthase .
As described above, LPS-activated microglia secrete the inflammatory compound, NO. EGCG decreases NO secretion and induction of iNOS protein in MO . Since the iNOS promoter contains a NF-KB-binding region, EGCG may act by its ability to inhibit nuclear translocation of NF-kB via inhibition of the proteosomal degradation of IkB. It also scavenges NO .
Peroxynitrite is produced by the interaction of NO with superoxide. It is an oxidizing/nitrating species that induces lipid peroxidation, modifies amino acids, causes DNA strand breakage/oxidation, and stimulates COX-2 activity. Peroxyni-trite increases Comet scores, indicative of DNA damage. EGCG decreases this damage and effectively scavenges peroxynitrite .
Much current interest is focused on interactions between the central nervous, endocrine, and immune systems. The latter is vital in protecting against microbial invasion and tumor growth; however, overstimulation or inappropriate targeting of immune effecter molecules can be pathological. Such potentially pathogenic molecules include ROS, RNS, and several cytokines, many of which are produced by MO, including microglia of the brain. Various CNS diseases involve the formation of pathogenic aggregates, abnormal functioning of neurotransmitters or their receptors, altered iron or Ca+2 homeostasis, impaired proteosomal activity, and mitochondrial dysfunction, resulting in cytochrome c release, activation of the caspase cascade, and apoptosis. EGCG affects all of these processes at least partially by altering the activity or production of key enzymes, via elements of intracellular signal transduction pathways such as PI3K, MAPK, and NF-kB, or by scavenging ROS, RNS, or iron.
EGCG is also beneficial for treating endocrine and autoimmune disorders. This polyphenol alters the production of a number of hormones, including those involved in cancers of the reproductive system, those regulating metabolism and weight, and those affecting disorders related to insulin. The immune system and its cytokines are also involved in the latter, particularly diabetes mellitus. EGCG also effects production of cytokines, including those which cause inflammatory responses, in ways that are only recently being explored.
In summary, EGCG makes multiple contributions to human health using a variety of mechanisms and via multiple intracellular pathways. It is only one of a number of polyphenols present in plant-derived alternative medicinal materials. These compounds and the foods/beverages/plant extracts that contain them promise to continue to help mankind to overcome diseases and improve the quality of life well into the future.
1. Mandel SA, Avramovich-Tirosh Y, Reznichenko L, Zheng H, Weinreb O, Amit T, Youdim MBH (2005) Neurosignals 14:46-60
2. Kalfon L, Youdim, MBH, Mandel SA (2007) J Neurochem 100:992
3. Weinreb O, Mandel S, Amit T, Youdim MBH (2004) J Nutr Biochem 15:506
4. Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC (2003) FASEB J 17:1913
5. Beltz LA, Bayer DK, Moss AL, Simet IM (2006) Anti-Cancer Agents Medicin Chem 6:389
6. Chou C-W, Huang W-J, Tien L-T, Wang S-J (2007) Synapse 61:889
7. Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI (2001) Life Sci 70:603
8. Porat Y, Abramowitz A, Gazit E (2006) Chem Biol Drug Des 67:27
9. Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimatsu F, Kitamoto T (2002) J Neurochem 82:1137
10. Bastianetto S, Yao Z-X, Papadopoulos V, Quirion R (2006) Eur J Neurosci 23:55
11. Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, Jin S, Takada N, Komatsu Y, Suzumura A (2008) FASEB J 22:online 1/15/08
12. Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MBH (2006) Mol Nutr Food Res 50:229
13. Choi J-Y, Park C-S, Kim D-J, Cho M-H, Jin B-K, Pie J-E, Chung W-G (2002) Neuro Toxicol 23:367
14. Lu H, Meng X, Yang CS (2003) Drug Metabol Disposal 31:572
15. Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Nat Med 2:1017
16. MaherP (2001) J Neurosci 21:2929
17. Chan DKY, Woo J, Ho SC, Pang CP, Law LK, Ng PW, Hung WT, Kwok T, Hui E, Orr K, Leung MF, Kay R (1998) J Neurol Neurosurg Psyc 65:781
18. Romero E, Cha G-H, Versteken P, Ly CV, Hughes RE, Bellen HJ, Botas J (2008) Neuron 57:27
19. Koh S-H, Lee SM, Kim HY, Lee K-Y, Lee YJ, Kim H-T, Kim J, Kim M-H, Hwang MS, Song C, Yang K-W, Lee KW, Kim SH, Kim O-H (2006) Neurosci Lett 395:103
20. Lee S-R, Suh S-I, Kim S-P (2000) Neurosci Lett 287:191
21. Sutherland BA, Shaw OM, Clarkson AN, Jackson DM, Sammut IA, Appleton I (2005) FASEB J 19:258
22. Matsuoka Y, Hasegawa H, Okuda S, Muraki T, Uruno T, Kubota K (1995) J Pharmacol Exp Ther 274:602
23. Kakuda T (2002) Biol Pharmacol Bull 25:1513
24. Sato Y, Nakatsuka H, Watanake T, Hisamichi S, Shimizu H, Fujisaku S, Ichinowatari Y, Ida Y, Suda S, Kato K, Ikeda M (1989) Tohoku J Exp Med 157:337
25. Townsend PA, Scarabelli TM, Pasini E, Gitti G, Menegazzi M, Suzuki H, Knight RA, Latch-man DS, Stephanou A (2004) FASEB J 18:1621
26. Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel P-M, Infante-Duarte C, Brocke S, Zipp F (2004) J Immunol 173:5794
27. Kira, J-I (2003) Lancet Neurol 2:117
28. Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC (1997) Neurochem Res 22:419
29. Campbell EL, Chebib M, Johnston GA (2004) Biochem Pharmacol 68:1631
30. Vignes M, Maurice T, Lante F, Nedjar M, Thethi K, Guiramand J, Recasens M (2006) Brain Res 1110:102
31. Adachi N, Tomonaga S, Tachibana T, Denbow DM, Furuse M (2006) Eur J Pharmacol 531:171
32. Unno K, Takabayashi F, Yoshida H, Choba D, Fukutomi R, Kikunaga N, Kishido T, Oku, N, Hoshino M (2007) Biogerontology 8:89
33. Unno K, Takabayashi F, Kishido T, Oku N (2004) Exp Gerontol 39:1027
34. Haque AM, Hashimoto M, Karakura M, Tanabe Y, Hara Y, Shido O (2006) J Nutr 136:1043
35. Kuriyama S, Hozawa A, Ohmori K, Shimazu T, Matsui T, Ebihara S, Awata S, Hagatomi R, Arai H, Tsuji I (2006) Am J Clin Nutr 83:355
36. Giunta B, Obregon D, Hou H, Zeng J, Sun N, Nikolic V, Ehrhart J, Shytle D, Fernandez, F, Tan J (2006) Brain Res 1123:216
37. Jeong H-S, Kim Y-S, Park J-S (2005) Brain Res 1047:267
38. Homma T, Hirai K, Hara Y, Katayama Y (2001) Neurosci Lett 309:93
39. Tseng W-P, Lin-Shiau S-Y (2003) Neurochem Int 42:333
40. Bae JH, Mun KC, Park WK, Lee S-R, Suh S-I, Baek WK, Yim M-B, Kwon TK, Song D-K (2002) Biochem Biophy Res Comm 290:1506
41. Kao Y-H, Hiipakka R A, Liao S (2000) Endocrinol 141:980
42. Kuruto-Niwa R, Inoue S, Ogawa S, Muramatsu M, Nozawa R (2000) J Agric Food Chem 48:6355
43. Li C, Allen A, Kwagh J, Doliba NM, Qin W, Najah H, Collins HW, Matschinsky FM, Stanley CA, Smith TJ (2006) J Biol Chem 281:10214
44. Collins QF, Liu H-Y, Pi J, Liu Z, Quon MJ, Cao W (2007) J Biol Chem 282:30143.
45. Shimada M, Mochizuki K, Sakurai N, Goda T (2007) Biosci Biotechnol Biochem 71:2079
46. Anton S, Melville L, Rena G (2007) Cellular Signal 19:378
47. Li R, Huang Y-G, Fang D, Le W-D (2004) J Neurosci Res 78:723
48. Haqqi TM, Anthony DD, Gupta S, Ahmad N, Lee M-S, Kumar GK, Mukhtar H (1999) Proc Natl Acad Sci USA 96:4524
49. Hsu SD, Dickinson DP, Qin H, Borke J, Ogbureke KUE, Winger JN, Camba AM, Bollag WB, Stoppler HJ, Sharawy MM, Schuster GS (2007) Autoimmunity 40:138
50. Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S (2001) J Neurochem 78:1073
51. Kishido T, Unno K, YoshidaH, Choba D, Fukutomi R, Asahina S, Iguchi K, Oku N, Hoshino M (2007) Biogerontology 8:423
52. Lin YL, Yin JK (1997) Mol Pharmacol 52:465
Was this article helpful?