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The Effects of the Green Tea Polyphenol Epigallocatechin Gallate on the Central Nervous, Endocrine, and Innate Immune Systems

Lisa A. Beltz

Abstract The central nervous, endocrine, and immune systems interact at several levels, including cell surface and intracellular molecules as well as compounds facilitating intercellular communication. Molecules produced by components of the immune system, such as reactive oxygen and nitrogen species and some cytokines secreted by brain microglia, may induce disorders of the nervous and endocrine systems if present in excess. Pathologic conditions of these three systems, including neurodegenerative diseases, anxiety, memory loss, ischemia, multiple sclerosis, alterations in weight and metabolism, diseases of insulin dysregulation, and several autoimmune disorders, have several common themes such as changes in iron/Ca+2 levels, altered proteosomal activity, mitochondrial dysfunction, and activation of the caspase cascade, leading to apoptosis. The green tea polyphenol epigallocatechin gallate (EGCG) has beneficial activity in a number of human diseases. It mitigates some of the above-listed damage in part by altering intracellular signal transduction pathways, by scavenging reactive oxygen and nitrogen species and iron, and by affecting cytokine production and expression of neurotransmitters or their receptors. This chapter presents these activities of EGCG and how they affect diseases of these related physiological systems.

Keywords Epigallocatechin gallate • Neurodegenerative diseases • Autoimmune diseases • Endocrine diseases • Reactive oxygen species • Cytokines

9.1 Introduction

Polyphenolic compounds from a variety of plants commonly utilized as food or beverage sources have been the focus of great interest in both the general populace and the scientific community. They bestow many benefits to human health and

Department of Biology, University of Northern Iowa, 901 Campbell Cr., NE Massillon, OH 44646, USA

e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4-9, © Springer-Verlag Berlin Heidelberg 2009

thus have great potential as alternative medicine sources. Green tea extract, derived from leaves of Camelia senensis, contains several such polyphenols, the most abundant of which is epigallocatechin gallate (EGCG). This compound has favorable activity in a wide variety of human disease states, including cancer, cardiovascular disorders, obesity, bacterial and viral infections, neurological disorders, and other more localized conditions. This chapter focuses on the effects of EGCG upon the hypothalamus-pituitary-adrenal axis, which encompasses the central nervous system (CNS), the endocrine system, and the immune system, with particular emphasis upon pathological conditions.

9.2 The Effects of EGCG on the Central Nervous System

The pathology of neurodegenerative diseases has several common, interrelated features, including excessive cytoplasmic Ca+2 levels, increased production of reactive oxygen species (ROS), dysfunction of the ubiquitin-proteosomal degradative system, mitochondrial dysfunction, cytochrome c release/initiation of the caspase cascade, and neuronal injury or death by apoptosis. Neurotransmitters or their receptors are also commonly involved. One major contributory factor is abnormal iron regulation; protective factors include protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3'-OH kinase (PI3K)/AKT activation [1]. The effect of EGCG on these processes will be discussed throughout the chapter (also see Table 9.1).

A number of factors are directly involved in initiating apoptosis in neurons, including cytochrome c release from mitochondria, caspase activation, and proapop-totic (Bad, Bax, Bid, Bim)/antiapoptotic (Bcl-2, Bcl-XL) proteins. Proapoptotic proteins increase mitochondrial permeability, resulting in decreased membrane potential and cytochrome c release. Levels of these proteins are regulated by proteosomal degradation. Exogenous EGCG rapidly decreases intracellular Bad levels in human neuroblastoma cells via a pathway utilizing proteosomes and PKC [2]. Oral administration of EGCG increases murine hippocampal levels of PKC and induces its membrane translocation in neuroblastoma cells [1, 3]. EGCG additionally decreases Bax expression and increases the Bcl-2:Bax ratio and Bad phosphorylation by signals involving MAPK and Akt in other cells [1, 4]. MAPK may function by activating stress-related genes, including the phase II drug-metabolizing enzyme glutathione-s-transferase, known to be stimulated by EGCG [5]. Decreased neuronal apoptosis by EGCG may involve decreased expression of proapoptotic genes, including caspase-1, mdm2, p21, and TNF-related apoptosis-inducing ligand, rather than increased antiapoptotic gene activity [3].

9 Effects of the Green Tea Polyphenol Epigallocatechin Gallate Table 9.1 Processes involving diseases of the CNS affected by EGCG

Processes decreased by EGCG*

Processes increased by EGCG*

Lipid peroxidation (1, 2)**

Xanthine oxidase activity (2)

LDL oxidation (2)

Oxidative DNA damage (3)

nNOS and iNOS activation (4)

Aggregation of hyperphosphorylated tau (1)

Holo-APP activity (1)

P-amyloid formation (1)

Catechol-O-methyltransferase activity (4)

a-synuclein (4)

Glutamate receptor activity (1, 4, 5, 6, 7) Excessive cytoplasmic Ca+2 (1, 4, 5, 7, 8) NF-kB activation (4, 5) JAK/STAT activation (2, 6) TNF-a production (5, 6) Proteosomal activity (5) Plasma cortisone levels (9)

Superoxide dismutase activity (1, 4, 7, 8)

Iron regulatory proteins (1,4)

Mitochondrial complex IV activity (2)

5-Amyloid precursor protein formation (1)

a-Secretase activity (1)

HIF-1 production (1)

Dopamine levels (4)

Tyrosine hydrolase activity (4)

Citrate synthase activity (2)

GABAa receptor activity (9)

PKC activity (1)

PI3K activity (7)

pAKT activity (7)

* Processes involved in disease causation in bold; those involved in protective activity in normal font.

** Diseases affected by these processes. 1 = Alzheimer's disease, 2 = ischemia, 3 = age-associated memory loss, 4 = Parkinson's disease, 5 = multiple sclerosis, 6 = HAD, 7 = ALS, 8 = HD, 9 = anxiety

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