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Grant Abstract

Grant Number: 1R21AT003396-02

Abstract: DESCRIPTION (provided by applicant): (-)-Epigallocatechin-3-gallate (EGCG) is a potent antioxidant of the flavan-3-ol family of polyphenolic compounds and is found enriched in green tea from the plant Camellia sinensis. EGCG is a potent inhibitor of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The specific aims of this proposal seek to provide the pre-clinical data needed to design clinical trials of EGCG in multiple sclerosis and to explore its neuroprotective mechanism of action. The proposal has two specific aims: 1) To verify that EGCG inhibits EAE and is neuroprotective in the presence of inflammatory infiltrate, and to determine the pharmacokinetics of orally administered EGCG; 2) To determine whether EGCG protects SH-SY5Y neuroblastoma cells by inhibition of the mitochondrial mediated cell death pathways. The effects of EGCG on EAE will be determined following administration of varying concentrations of EGCG in drinking water. Pathological assessments will be made of demyelination and axonal damage in white matter of spinal cords from treated and untreated mice by morphometric analysis following toluidine blue staining and confirmation of axonal injury by immunohistochemical detection of phosphorylated neurofilaments. Phenotype and quantification of inflammatory cell infiltrate will be performed by immunohistochemical analyses. Plasma levels of EGCG in mice receiving varying doses of EGCG will be determined by high performance liquid chromatography and the plasma levels will be correlated with clinical and histologic benefit. In vitro examination of the neuroprotective effects of EGCG will include induction of cell death with the following: TNF-alpha, L-glutamic acid, an NO donor (NOC-12), and hydrogen peroxide. Extrinsic and intrinsic cell death pathways will be assessed by the measuring cytosolic cytochrome c, cleaved and uncleaved caspases-9, -3, and -8, and cleaved and uncleaved Bid to determine at what point EGCG inhibits cell death. Relevance to public health: We are assessing the neuroprotective capacity of EGCG by assessing its effects in an animal model of MS and characterizing its mechanism of action in vitro. The purpose of this research is to provide the groundwork necessary to develop EGCG as a novel neuroprotective treatment for the human disease, multiple sclerosis.

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