Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). About 80% of MS patients start the disease as a form of Relapsing Remitting MS (RRMS) that is characterized by frequent inflammatory attacks followed by spontaneous recovery. However, about 10 years after disease onsite, 50% of the patients enter into secondary progressive MS (SPMS). At this stage, inflammation is limited, however, neurological decline continues. Therefore, both dysregulated immune function and neurodegeneration seem to contribute to the pathogenesis of MS.
Clinical trials showed that Dimethyl Fumarate (DMF), a novel oral treatment for MS, significantly reduced gadolinium enhancing lesions in Relapsing-Remitting MS (RRMS). The safety record, efficacy and oral availability of DMF makes it potentially more beneficial to MS patients than currently available therapies. Yet, neither the molecular mechanism nor the potential neuroprotective effect of DMF has been fully investigated.
One interesting observation from the Phase II clinical trial was a reduction in IFN-γ producing CD4+ T cells (Th1) in fumarate treated patients. Because Th1 cells are considered to be the pathogenic cells in MS, this clinical observation may have identified one mechanism of action of DMF. The first part of my graduate work was dedicated to
understanding the cellular and molecular mechanism behind this clinical observation. Using dendritic cell generated both in vitro and in vivo, we demonstrate that DMF inhibits dendritic cell (DC) maturation by significantly reducing proinflammatory cytokine production and the expression of MHC class II, CD80 and CD86. Importantly, this immature DC phenotype generated fewer activated T cells that were characterized by decreased IFN-γ and IL-17 production. Further molecular studies demonstrate that DMF exerts its effects on DCs via suppression of both Nuclear Factor ¿¿¿¿B (NF-¿¿¿¿B) and Extracellular signal-Regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress activated Kinase 1(MSK1) signaling and upregulation of Heme Oxygenase-1 (HO-1). This part of my study established a cellular and molecular mechanism through which DMF treatment led to a reduction in Th1 population in patients with MS.
In addition to its immunoregulatory effects, DMF may have neuroprotective properties. It was demonstrated that Nrf-2, a critical transcription factor involved in combating oxidative stress, was activated in astrocytes after DMF treatment. However, one could argue that the Experimental Autoimmune Encephalomyelitis (EAE) animal used in the previous study was problematic as this model is characterized by massive inflammation and that DMF has immunoregulatory effects. Therefore, it remains unclear if the beneficial effect of DMF in EAE is exclusively through its immunoregulatory effects or neuroprotective effects or a combination of both. To exclude the effects of DMF on inflammation, an excitotoxic model induced by microinjection of AMPA directly into mouse spinal cord was utilized in our study.
Naïve mice were fed with DMF (125mg/Kg/day) for three days followed by microinjection of AMPA. Our results demonstrate that DMF pre-treatment reduces neuronal loss and improves locomotor activity as compared to vehicle-treated mice, suggesting a potential neuroprotective role of DMF. Furthermore, we also demonstrate that HO-1, an inducible enzyme downstream of Nrf-2 that also has anti-oxidative properties, was unregulated by DMF. This may suggest HO-1 as a potential target of DMF in the CNS.
Taken together, this translational research enhances our understanding of the cellular and molecular mechanisms of DMF, providing mechanistic foundation for the application of DMF in treating patients with MS. Additionally; this study helps us gain knowledge of MS pathogenesis, which may further favor the development of novel therapies in the future.