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Nrf2: A Novel Biomarker of Disease Severity and Target for Therapeutic Intervention in Multiple Sclerosis

Letterio, J;

The overall aim of this current proposal is to explore diverse triterpenoids that will enable careful dissection of the Nrf2-dependent and independent pathways mediating triterpenoid neuroprotection and will define a novel class of potent and effective therapeutic and chemo preventive agents for multiple sclerosis. In our earlier report we reported the successful large scale (in gram quantity) isolation of Bryonolic acid from zucchini plant (Cucurbita pepo L.) roots and characterized its activity. We also applied Diversity Oriented Synthesis to Bryonolic acid to rearrange skeletal structure and analyzed the specificity and activity of skeletally diverse triterpenoids in vivo and in vitro including its potential role in suppression of disease symptoms in EAE (Experimental Autoimmune Encephalomyelitis). In the current report we: 1) characterize the Nrf2-targeted antioxidant properties of the natural triterpenoid Celastrol, isolated from the root extracts of Tripterygium wilfordii (Thunder god vine); 2) standardize an imaging technique used to capture T cell/APC interaction and infiltration in CNS during the disease course of EAE; and finally 3) characterize the potential benefit of CDDO-DFEA treatment in EAE by influencing T cell/APC interactions.