Parkinson's disease is a progressive disorder involving the degeneration of dopamine-producing neurons in the substantia nigra, resulting in symptoms such as resting tremor, bradykinesia, rigidity, gait disturbance, and postural instability . Tyrosine hydrolase (TH) is critical to the formation of L-dopa, and thus dopamine, and decreases in its activity occur in animal models of Parkinson's disease. In a murine model of Parkinson's disease, oral administration of EGCG inhibited damage to dopaminergic neurons, preserving numbers of TH-positive cells and TH activity in the striatum and preventing loss of dopamine and its metabolites . Dopamine is a substrate of catechol-O-methyltransferase. Since EGCG inhibits this enzyme, it may additionally increase dopamine levels in synapses by this mechanism .
Reactive nitrogen species (RNSs) generated by neuronal nitric oxide synthase (nNOS) are involved in Parkinson's disease pathogenesis since enzyme inhibition or absence of its gene promotes disease resistance . EGCG inhibits activity of nNOS in the CNS and inducible NOS (iNOS) in macrophages (discussed below), perhaps by negatively regulating nuclear factor-KB (NF-kB), a transcription factor to which these genes' promoters respond [5, 13].
A number of polyphenols, including EGCG, function as antioxidants at low concentrations . Some of their actions involve scavenging ROSs (discussed below) and induction of endogenous antioxidants via PKC . ROS generation via iron dysregulation plays a role in Parkinson's disease. Toxic a-synuclein aggregates form after exposure to redox-active iron; both occur within Lewy bodies, characteristic of Parkinson's disease . As in Alzheimer's disease, iron also regulates degradation of IRP in Parkinson's disease. Decreased amounts of IRP lead to decreased transcription of the transferrin receptor, and thus increases in the iron transport protein, ferritin. Mice lacking the IRP gene accumulate iron in their substriatia and develop symptoms of Parkinson's disease, including tremor and bradykinesia. EGCG prevents accumulation of a-synuclein and decreases removal of IRP in murine models of Parkinson's disease . Iron chelation may thus contribute to EGCG's neuropro-tective effects in Parkinson's disease.
Epidemiological studies support the importance of green tea and EGCG in reducing incidence of Parkinson's disease. Studies in Hong Kong found that regular green tea consumption (particularly at least 2 cups per day) correlated with decreased risk for disease development [13, 17]. Rates of Parkinson's disease are five to ten times lower in China and Japan (high consumption of green tea) than the Western world (black tea favored). Green tea contains 10- to 20-fold more EGCG than black tea, derived from the same plant.
9.2.3 Huntington's Disease
Huntington's disease is a dominantly inherited CNS disorder characterized by severe cognitive, motor, and psychiatric manifestations. A prime feature of this disease is the expansion of CAG repeats in the amino terminus of the huntingtin protein (htt), resulting in glutamine-expanded htt. Wild-type htt is involved in many cellular processes, including neurotransmission. The altered protein forms aggregates in neuronal nuclei in addition to contributing to altering synaptic function by inducing abnormal responses to stimulation via the NMDA glutamate receptor . Animal models containing "knockin" glutamine-expanded htt experience loss of neurons in the striatum and cortex. In such a Drosophila model, increased synaptic neurotransmitter release efficiency occurred in association with elevated cytoplasmic Ca+2 levels. Blocking synaptic transmission or voltage-gated Ca+2 channels reduces neurodegeneration . EGCG alters neurotransmitter levels and activity of their receptors, as well as regulates Ca+2 homeostasis (see below).
As stated above for Alzheimer's and Parkinson's diseases, iron dysregulation and the resultant ROS generation are also involved in neuronal injury via oxidative stress in Huntington's disease. The iron-chelating and antioxidant properties of EGCG thus may potentially be beneficial for this disease as well .
9.2.4 Amyotropic Lateral Sclerosis (ALS)
Excessive Ca+2 levels, ROS, and abnormal iron disposition are features of ALS. Elevated Ca+2 influx in ALS is at least partially due to glutamate binding the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor . EGCG can alter glutamate production/receptor interactions, inhibit abnormal accumulation of cyto-plasmic Ca+2, chelate iron, and decrease oxidative stress. It may thus be of benefit in the treatment of this disease as well as the previously mentioned neurological disorders .
A murine model for human ALS uses transgenic mice expressing mutated Cu/Zn-superoxide dismutase gene. These mice are considered to be symptomatic when their limbs shake while suspended in air; disease progresses to the point at which they can no longer right themselves. Mice ingesting EGCG had delayed symptom onset and prolonged lifespans . Their spinal cords contained higher levels of survival signals, such as PI3K, pAKt, and pGSK-30.
9.2.5 Ischemic Conditions/Stroke
ROS and lipid peroxidation play causal roles in neuronal injury following ischemia and reperfusion of the brain. When transient global ischemia was induced in Mongolian gerbils or Wistar rats by occlusion of the carotid arteries, hippocampal CA1 region pyramidal neurons were severely damaged, becoming pyknotic with chromosomal condensation [20, 21]. Intraperitoneal administration of EGCG immediately following ischemic insult reduced the damage and infarct size. The protective mechanism is believed to involve the ability of EGCG to inhibit xanthine oxidase and reduce the activity and protein levels of iNOS (see below). On the other hand, nNOS and endothelial NOS activities increased; the latter may have a protective effect via increased cerebral circulation. In the rat system, EGCG also maintained activities of mitochondrial complex IV and citrate synthase. Ischemia-related memory dysfunction also decreased in mice .
Arteriosclerosis is a major factor in ischemic cerebrovascular disease. Oxidative alterations of cholesterol-containing low-density lipoproteins (LDL) occur; these oxidized particles are subsequently ingested by macrophages, which transform into foam cells. EGCG prevents LDL oxidation .
In a large study of nondrinking/nonsmoking women aged > 40 years in Japan, daily green tea consumption lowered risks of stroke occurrence and mortality, but not hypertension, even in those who ingested high Na+2 levels daily . Activation of the JAK/STAT pathway may increase neuronal pathology in stroke; this pathway is inhibited by EGCG .
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