Green Tea Epigallocatechin-3-Gallate Mediates T Cellular NF-κB Inhibition and Exerts Neuroprotection in Autoimmune Encephalomyelitis

Abstract

Recent studies in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), point to the fact that even in the early phase of inflammation, neuronal pathology plays a pivotal role in the sustained disability of affected individuals. We show that the major green tea constituent, (−)-epigallocatechin-3-gallate (EGCG), dramatically suppresses EAE induced by proteolipid protein 139–151. EGCG reduced clinical severity when given at initiation or after the onset of EAE by both limiting brain inflammation and reducing neuronal damage. In orally treated mice, we found abrogated proliferation and TNF-α production of encephalitogenic T cells. In human myelin-specific CD4+ T cells, cell cycle arrest was induced, down-regulating the cyclin-dependent kinase 4. Interference with both T cell growth and effector function was mediated by blockade of the catalytic activities of the 20S/26S proteasome complex, resulting in intracellular accumulation of IκB-α and subsequent inhibition of NF-κB activation. Because its structure implicates additional antioxidative properties, EGCG was capable of protecting against neuronal injury in living brain tissue induced by N-methyl-d-aspartate or TRAIL and of directly blocking the formation of neurotoxic reactive oxygen species in neurons. Thus, a natural green tea constituent may open up a new therapeutic avenue for young disabled adults with inflammatory brain disease by combining, on one hand, anti-inflammatory and, on the other hand, neuroprotective capacities.

Oxidative Stress and Neurotoxicity

“…Evidence for a pathogenic role of ROS in MS pathology has led to the employment of several antioxidant strategies in an effort to ameliorate EAE (293,300,301). With the acceptance of the possibility that active oxidative stress contributes to the disease process, there is increasing focus on developing therapies directed at upregulating antioxidant enzyme systems (302,303) or production of endogenous antioxidants (304).…”

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

“…In support of this, recent animal studies have shown that green tea intake helps to prevent age-related cognitive deficits (Table 2), particularly after long-term administration of green tea (approximately 6 months), which was shown to positively influence memory and learning in both normally aged and senescence-accelerated animals (96,146,160) . Tea flavonoids have been reported to be potent Fe chelators, radical scavenging agents and to have antiinflammatory activities (161)(162)(163)(164)(165)(166) . In addition to these effects, recent studies have also indicated that they are capable of modulating signal transduction pathways and of regulating gene expression, and that these effects may also contribute to the neuroprotective effects of these compounds (29,167) .…”

Cognitive deficit associated with cholinergic and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats

“…Neuroprotection as a Therapeutic Target for MS. Neural damage in MS could be directly due to inflammation (43) or result from loss of trophic support normally provided to axons by myelin or glia. Consequently, neuroprotection is considered a novel target for MS, and different drugs and molecules, including statins, green tea epigallocatechin-3-gallate, and erythropoietin (44)(45)(46), have been indicated as effective in experimental models of the disease. Here, we indicate that chronic administration of selective acetylcholinesterase inhibitors that are approved for AD treatment, at a dosage effective in increasing acetylcholine release in the hippocampus and cortex of aged rats (21), restores ChaT activity and performance in the water maze test in EAE rats.…”