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      Dual Beneficial Effects of (-)-Epigallocatechin-3-Gallate on Levodopa Methylation and Hippocampal Neurodegeneration: In Vitro and In Vivo Studies

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          Abstract

          Background

          A combination of levodopa (L-DOPA) and carbidopa is the most commonly-used treatment for symptom management in Parkinson's disease. Studies have shown that concomitant use of a COMT inhibitor is highly beneficial in controlling the wearing-off phenomenon by improving L-DOPA bioavailability as well as brain entry. The present study sought to determine whether (-)-epigallocatechin-3-gallate (EGCG), a common tea polyphenol, can serve as a naturally-occurring COMT inhibitor that also possesses neuroprotective actions.

          Methodology/Principal Findings

          Using both in vitro and in vivo models, we investigated the modulating effects of EGCG on L-DOPA methylation as well as on chemically induced oxidative neuronal damage and degeneration. EGCG strongly inhibited human liver COMT-mediated O-methylation of L-DOPA in a concentration-dependent manner in vitro, with an average IC 50 of 0.36 µM. Oral administration of EGCG moderately lowered the accumulation of 3- O-methyldopa in the plasma and striatum of rats treated with L-DOPA + carbidopa. In addition, EGCG also reduced glutamate-induced oxidative cytotoxicity in cultured HT22 mouse hippocampal neuronal cells through inactivation of the nuclear factor κB-signaling pathway. Under in vivo conditions, administration of EGCG exerted a strong protective effect against kainic acid-induced oxidative neuronal death in the hippocampus of rats.

          Conclusions/Significance

          These observations suggest that oral administration of EGCG may have significant beneficial effects in Parkinson's patients treated with L-DOPA and carbidopa by exerting a modest inhibition of L-DOPA methylation plus a strong neuroprotection against oxidative damage and degeneration.

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          Most cited references 55

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          NF-kappaB activation by reactive oxygen species: fifteen years later.

          The transcription factor NF-kappaB plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappaB may be activated by H(2)O(2), several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to IkappaBalpha Y42 phosphorylation independently of IkappaB kinase (IKK), recent findings suggest that H(2)O(2) activates NF-kappaB mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and (1)O(2)) and reactive nitrogen species on NF-kappaB activation. Finally, we critically review the recent data highlighting the role of ROS in NF-kappaB activation by proinflammatory cytokines (TNF-alpha and IL-1beta) and lipopolysaccharide (LPS), two major components of innate immunity.
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            Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions.

            Increasing interest in the health benefits of tea has led to the inclusion of tea extracts in dietary supplements and functional foods. However, epidemiologic evidence regarding the effects of tea consumption on cancer and cardiovascular disease risk is conflicting. While tea contains a number of bioactive chemicals, it is particularly rich in catechins, of which epigallocatechin gallate (EGCG) is the most abundant. Catechins and their derivatives are thought to contribute to the beneficial effects ascribed to tea. Tea catechins and polyphenols are effective scavengers of reactive oxygen species in vitro and may also function indirectly as antioxidants through their effects on transcription factors and enzyme activities. The fact that catechins are rapidly and extensively metabolized emphasizes the importance of demonstrating their antioxidant activity in vivo. In humans, modest transient increases in plasma antioxidant capacity have been demonstrated following the consumption of tea and green tea catechins. The effects of tea and green tea catechins on biomarkers of oxidative stress, especially oxidative DNA damage, appear very promising in animal models, but data on biomarkers of in vivo oxidative stress in humans are limited. Larger human studies examining the effects of tea and tea catechin intake on biomarkers of oxidative damage to lipids, proteins, and DNA are needed.
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              Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration.

              Fluoro-Jade B, like its predecessor Fluoro-Jade, is an anionic fluorescein derivative useful for the histological staining of neurons undergoing degeneration. However, Fluoro-Jade B has an even greater specific affinity for degenerating neurons. This notion is supported by the conspicuous staining of degenerating neuronal elements with minimal background staining. This improved signal-to-noise ratio means that fine neuronal processes including distal dendrites, axons and axon terminals can be more readily detected and documented. Although the staining time and dye concentration are reduced, the method is as rapid, simple and reliable as the original Fluoro-Jade technique. Like Fluoro-Jade, Fluoro-Jade B is compatible with a number of other labeling procedures including immunofluorescent and fluorescent Nissl techniques.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                5 August 2010
                : 5
                : 8
                Affiliations
                Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America
                University of Nebraska, United States of America
                Author notes

                Conceived and designed the experiments: KSK BTZ. Performed the experiments: KSK YW NY MF BTZ. Analyzed the data: KSK SCB BTZ. Contributed reagents/materials/analysis tools: BTZ. Wrote the paper: KSK BTZ.

                Article
                10-PONE-RA-16178R2
                10.1371/journal.pone.0011951
                2916818
                20700524
                Kang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 14
                Categories
                Research Article
                Mental Health
                Neurological Disorders
                Neurological Disorders/Neuropharmacology

                Uncategorized

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