Mechanisms and effects of phytoestrogen treatment in autoimmune optic neuritis

University Of North Texas Hlth Sci Ctr, Fort Worth TX

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Elevated endothelin-1 (ET-1) in the optic nerve may contribute to the pathogenesis of autoimmune optic neuritis, a common early manifestation of multiple sclerosis (MS) that can be modeled in rats with myelin oligodendrocyte glycoprotein (MOG) peptide-induced autoimmune optic neuritis. Like its parent disease MS, autoimmune optic neuritis presents a coordinated but diverse set of immune, myelin, and axon pathologies affecting many cell types. Not only is ET-1 elevated in plasma and cerebral spinal fluid (CSF) of patients with MS, it is also capable of inducing most (or all) MS-associated pathologies, including aberrant fast axonal transport, under certain conditions. Answering the critical question of whether elevated ET-1 is required for the pathogenesis of these diseases has been hampered by an inability of endothelin receptor antagonists to cross the blood-brain/retinal barrier, requiring invasive methods unacceptable for routine treatment of a chronic human disorder where an orally-available treatment would be ideal. Fortunately, a recently discovered orally-available dietary substance may be useful. Trans-resveratrol is the phytoestrogen in red wine and peanuts believed responsible for the "French Paradox" through the suppression of ET-1 synthesis. Trans-resveratrol crosses the blood- brain/retinal barrier and its suppression of ET-1 synthesis in the CNS is one possible mechanism for red wine's reported ability to improve symptoms of autoimmune optic neuritis. Therefore, this application has the following specific aims: 1) To test the hypothesis that trans-resveratrol administration decreases the levels of ET-1 in optic nerve and that ET-1 levels significantly correlate with the observed MS-like pathologies in autoimmune optic neuritis. 2) To test the hypothesis that trans-resveratrol administration can reverse changes in anterograde fast axonal transport that are believed to cause axon pathologies in autoimmune optic neuritis. 3) To test the hypothesis that trans-resveratrol administration delays the development of seven different MS-associated histopathologies (affecting astrocytes, microglia, leukocytes, oligodendrocytes and neurons) during the pathogenic phase of autoimmune optic neuritis in rats. This would be predicted if trans-resveratrol inhibits CNS synthesis of ET-1 and elevation of ET-1 is a critical step for the pathogenesis of autoimmune optic neuritis. Autoimmune optic neuritis is a common early manifestation of multiple sclerosis (MS). This project evaluates whether trans-resveratrol, an orally available substance found in peanuts and red wine, can prevent, delay, and/or ameliorate the development and progression of autoimmune optic neuritis in vivo. Favorable results from this study may define a mechanism to improve clinical outcomes for MS patients. [unreadable] [unreadable] [unreadable]