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Abstract
Grant Number: 5R21AT003605-02 Project Title: Mechanisms and effects of phytoestrogen treatment in autoimmune optic neuritis
PI Information: Name Title STOKELY, MARTHA ELISE. mstokely@hsc.unt.edu Abstract: 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.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
optic neuritis, phytoestrogen
alcoholic beverage, amyloid protein, astrocyte, axon, base, blood, brain, cell type, cerebrospinal fluid, child rearing, concept, conditioning, emotion, endothelin, experimental allergic encephalomyelitis, family, fasting, glycoprotein, histopathology, human, kinesin, leukocyte, leukocyte activation /transformation, microglia, model, multiple sclerosis, myelin, myelinopathy, neuritis, neurofilament, neuron, neuronal transport, oligodendroglia, optic nerve, optics, parent, pathology, peanut, peptide, plasma, radioimmunoassay, receptor, retinaldehyde, role, sodium channel, spinal cord, suppression, visual perception
Institution: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR 3500 CAMP BOWIE BLVD. FORT WORTH, TX 761072699 Fiscal Year: 2008 Department: PHARMACOLOGY AND NEUROSCIENCE Project Start: 01-JUN-2007 Project End: 31-MAY-2009 ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE IRG: ZAT1