To develop a human in vitro model that allows us to study multiple sclerosis (MS) related injuries on human cortical neuronal progenitor stem cells (NSC) and to identify the effect of the immunomodulatory drug, Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on survival of injured NSC.

MS is an autoimmune disorder of central nervous system. DMF is used to treat relapsing-remitting MS. Few mechanisms of action have been described for both DMF and MMF, all involving the immune system. However, the effects of DMF and MMF within the human Central Nervous System (CNS) are not well understood.

We have utilized NSC derived from human induced pluripotent stem cells (iPSC) to study neurodegenerative mechanisms. We also studied the effect of DMF and MMF on primary human fetal neurons (hFN). Oxidative stress has been shown as a mechanism of neuronal injury in many neurodegenerative disease models. Oxidative stress was induced by short term H₂O₂ treatment. Cell viability and apoptosis was measured by LDH assay and Annexin V measurements, respectively.

Induction of oxidative stress by hydrogen peroxide resulted in 28% cell death in hFN. However, both DMF and MMF pre-treatment of hFN resulted in reduced cell death (18 and 16%, respectively). Next, we investigated the effect of fumarate pre-treatment on NSC derived from iPSC after oxidative stress induction. Pretreatment with both 20uM DMF and MMF significantly reduced H2O2-induced death.

Our results suggest that one of the mechanisms of action of fumarates within the CNS is the protection of neurons against oxidative stress-mediated injury. In addition, protection of NSC against oxidative stress may enhance NSC survival and differentiation, which is shown to be involved in CNS lesions repair.