UC Riverside

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS). Demyelination is a hallmark symptom of MS and leads to a decrease in neuronal, motor and cognitive function which significantly decreases quality of life. Current MS treatments are exclusively immunosuppressant and immunomodulatory with the goal of halting disease progression. For this reason, current treatments fail to address the loss of function associated with MS as well as the individual response to therapeutics. Recent studies have identified Estrogen as having ameliorating effects in MS, specifically Estrogen Receptor Beta (ERβ). ERβ ligands are potential therapeutics as they activate Estrogen’s neuroprotective and proliferating effects without the negative side effects exerted by ERα activation. Our lab identified two novel ERβ ligands, CAD-102 and CAD-110, as potential remyelinating therapeutics in MS. Previously, our lab has established a reliable Primary Mouse Oligodendrocyte (OL) culture model to assess efficacy of myelinating compounds in differentiating OL progenitor differentiation to mature OLs . While OL differentiation is important, efficacy of myelination compounds has to be confirmed using in vivo mouse models. Here I describe two reliable methods to assess the OPC differentiation and axon myelination efficacy of various compounds in vitro using primary mouse OLs in the presence of primary cortical mouse neurons as well as to assess differentiation efficacy in primary iPSC derived human OPCs. Using this method, I established CAD-102 and CAD-110’s superior OPC differentiation to OLs and axon myelination using primary OL-Neuron co-cultures when compared to known remyelinating agents like Bazedoxifene, Clemastine, LY500307, and ErB-041 as well as superior differentiation in primary iPSC derived human OPCs culture. These results establish the use of these culture models to screen superior remyelination agents.