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Dimethyl fumarate ameliorates myoclonus stemming from protein misfolding in oligodendrocytes
Cherie M Southwood1, Danielle M Garshott2, Chelsea R Richardson1
1Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract:
Multiple sclerosis (MS) is considered a primary autoimmune disease; however, this view is increasingly being challenged in basic and clinical science arenas because of the growing body of clinical trials' data showing that exclusion of immune cells from the CNS only modestly slows disease progression to disability. Accordingly, there is significant need for expanding the scope of potential disease mechanisms to understand the etiology of MS. Concomitantly, the use of a broader range of pre-clinical animal models for characterizing existing efficacious clinical treatments may elucidate additional or unexpected mechanisms of action for these drugs that augment insight into MS etiology. Herein, we explore the in vivo mechanism of action of dimethyl fumarate, which has been shown to suppress oxidative stress and immune cell responses in psoriasis and MS. Rather than studying this compound in the context of an experimental autoimmune-induced attack on the CNS, we have used a genetic model of hypomyelination, male rumpshaker (rsh) mice, which exhibit oligodendrocyte metabolic stress and startle-induced subcortical myoclonus during development and into adulthood. We find that myoclonus is reduced 30-50% in treated mutants but we do not detect substantial changes in metabolic or oxidative stress response pathways, cytokine modulation, or myelin thickness (assessed by anova). All procedures involving vertebrate animals in this study were reviewed and approved by the IACUC committee at Wayne State University.
Insights
Dimethyl fumarate reduced tremors in a genetic mouse model of hypomyelination. This study suggests potential non-immune mechanisms for multiple sclerosis (MS) treatments.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is traditionally viewed as an autoimmune disease, but clinical trial data suggests immune cell exclusion offers only modest benefits.
- This highlights a need to explore alternative disease mechanisms and pre-clinical models for understanding MS etiology.
- Dimethyl fumarate (DMF) is known to modulate oxidative stress and immune responses.
Purpose of the Study:
- To investigate the in vivo mechanism of action of dimethyl fumarate (DMF) in a genetic model of hypomyelination.
- To explore potential therapeutic effects of DMF beyond immune suppression in the context of neurological disorders.
- To utilize the rumpshaker (rsh) mouse model, which exhibits oligodendrocyte metabolic stress and myoclonus, to study DMF's effects.
Main Methods:
- DMF was administered to male rumpshaker (rsh) mice, a genetic model exhibiting hypomyelination and myoclonus.
- The study assessed the impact of DMF on myoclonus severity, metabolic stress, oxidative stress pathways, cytokine modulation, and myelin thickness.
- Animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC).
Main Results:
- Treatment with DMF resulted in a 30-50% reduction in myoclonus in the treated rumpshaker mice.
- No substantial changes were observed in metabolic or oxidative stress response pathways following DMF treatment.
- DMF treatment did not lead to significant alterations in cytokine modulation or myelin thickness in the studied model.
Conclusions:
- Dimethyl fumarate demonstrates efficacy in reducing neurological symptoms (myoclonus) in a genetic model of hypomyelination.
- The findings suggest that DMF may exert therapeutic effects through mechanisms independent of direct immune cell modulation or significant changes in oxidative stress.
- This research supports the exploration of non-immune and metabolic pathways in the development of treatments for conditions like multiple sclerosis.