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MMF induces antioxidative and anaplerotic pathways and is neuroprotective in hyperexcitability in vitro
Lukas Gola1, Laura Bierhansl1, Nicolas Hummel1
1Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
Abstract:
Hyperexcitability-induced neuronal damage plays a role both in epilepsy as well as in inflammatory brain diseases such as multiple sclerosis (MS) and as such represents an important disease pathway which potentially can be targeted to mitigate neuronal damage. Dimethyl fumarate (DMF) and its pharmacologically active metabolite monomethyl fumarate (MMF) are FDA-approved therapeutics for MS, which can induce immunosuppressive and antioxidant pathways, and their neuroprotective capacity has been demonstrated in other preclinical neurological disease models before. In this study, we used an unbiased proteomic approach to identify potential new targets upon the treatment of MMF in glio-neuronal hippocampal cultures. MMF treatment results in induction of antioxidative (HMOX1, NQO1) and anaplerotic metabolic (GAPDH, PC) pathways, which correlated with reduction in ROS production, increased mitochondrial NADH-redox index and decreased NADH pool, independent of glutathione levels. Additionally, MMF reduced glycolytic capacity indicating individual intra-cellular metabolic programs within different cell types. Furthermore, we demonstrate a neuroprotective effect of MMF upon hyperexcitability in vitro (low magnesium model), where MMF prevents glio-neuronal death via reduced ROS production. These results highlight MMF as a potential new therapeutic opportunity in hyperexcitability-induced neurodegeneration.
Insights
Monomethyl fumarate (MMF) protects brain cells from damage caused by hyperexcitability, a key factor in epilepsy and multiple sclerosis. This study reveals MMF
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Neuronal damage from hyperexcitability is implicated in epilepsy and inflammatory brain diseases like multiple sclerosis (MS).
- Dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) are FDA-approved MS therapies with known immunosuppressive and antioxidant properties.
- Previous studies suggest MMF's neuroprotective potential in preclinical neurological disease models.
Purpose of the Study:
- To identify novel molecular targets of monomethyl fumarate (MMF) using an unbiased proteomic approach in glio-neuronal hippocampal cultures.
- To investigate the metabolic and cellular effects of MMF treatment.
- To evaluate the neuroprotective efficacy of MMF against hyperexcitability-induced neuronal damage in vitro.
Main Methods:
- Unbiased proteomic analysis of MMF-treated glio-neuronal hippocampal cultures.
- Assessment of antioxidative and metabolic pathway induction (e.g., HMOX1, NQO1, GAPDH, PC).
- Measurement of reactive oxygen species (ROS) production, mitochondrial NADH-redox index, NADH pool, and glycolytic capacity.
- In vitro assessment of MMF's neuroprotective effect using a low magnesium-induced hyperexcitability model.
Main Results:
- MMF treatment induced antioxidative (HMOX1, NQO1) and anaplerotic metabolic (GAPDH, PC) pathways.
- MMF reduced ROS production, increased mitochondrial NADH-redox index, and decreased NADH pool, independent of glutathione levels.
- MMF decreased glycolytic capacity, suggesting cell-type-specific metabolic reprogramming.
- MMF demonstrated neuroprotection against hyperexcitability in vitro, preventing glio-neuronal death by reducing ROS production.
Conclusions:
- MMF modulates key metabolic and antioxidative pathways in glio-neuronal cells.
- MMF exhibits significant neuroprotective effects against hyperexcitability-induced damage by mitigating ROS production.
- MMF represents a promising therapeutic candidate for conditions involving hyperexcitability-induced neurodegeneration.
