The Role of Reactive Oxygen Species

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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 [5].

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 [51]. 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 [5]. It does so in neurons even in the presence of buthionine sulfoximine, an inhibitor of glu-tathione synthase [26].

9.4.3 The Role of Reactive Nitrogen Species

As described above, LPS-activated microglia secrete the inflammatory compound, NO. EGCG decreases NO secretion and induction of iNOS protein in MO [52]. 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 [5].

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 [5].

9.5 Conclusions

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.

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