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Neuroprotective and Anti-Inflammatory Effects of Dimethyl Fumarate, Monomethyl Fumarate, and Cannabidiol in Neurons
Alicia Sánchez-Sanz1, María José Coronado-Albi2, Rafael Muñoz-Viana3
1Neuroimmunology Unit, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, 28222 Madrid, Spain.
Abstract:
Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS) that can cross the blood-brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood, and there is a need to characterize whether DMF or its bioactive metabolite monomethyl fumarate (MMF) exerts neuroprotective properties. Moreover, the combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the neuroprotective and immunomodulatory effects of DMF, MMF, and CBD in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. Additionally, the three drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF modulated a greater number of inflammatory and Nrf2-related genes compared to MMF and CBD in both neurons and microglia. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients. Additionally, CBD shows potential as a neuroprotective agent.
Insights
Dimethyl fumarate (DMF) and cannabidiol (CBD) show neuroprotective effects in multiple sclerosis (MS) models by activating antioxidant pathways and reducing inflammation. Monomethyl fumarate (MMF) demonstrated fewer benefits, highlighting distinct mechanisms of action for MS treatment.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Dimethyl fumarate (DMF) is an immunomodulatory drug for multiple sclerosis (MS) with potential neuroprotective properties, though its mechanism and that of its metabolite monomethyl fumarate (MMF) require clarification.
- Cannabidiol (CBD) is explored as an adjuvant therapy to enhance neuroprotection.
Purpose of the Study:
- To compare the neuroprotective and immunomodulatory effects of DMF, MMF, and CBD in in vitro neuronal and microglial models.
- To investigate the activation of the Nrf2 antioxidant and NF-kB inflammatory pathways by these compounds.
Main Methods:
- In vitro study using neuronal and microglial cell cultures.
- Assessment of Nrf2 and NF-kB pathway activation.
- Measurement of nitric oxide production.
- Evaluation of neuronal apoptosis.
- Transcriptomic analysis.
Main Results:
- DMF and CBD activated the Nrf2 pathway in neurons, while MMF did not.
- DMF and CBD inhibited LPS-induced NF-kB activation in microglia; MMF did not.
- All three compounds reduced nitric oxide production in microglia and protected neurons from apoptosis.
- DMF modulated more inflammatory and Nrf2-related genes than MMF and CBD.
Conclusions:
- DMF and MMF exhibit distinct mechanisms of action, impacting their potential neuroprotective efficacy in MS.
- CBD demonstrates significant neuroprotective potential as a standalone agent or adjuvant therapy.
- Understanding these differential effects is crucial for optimizing therapeutic strategies in multiple sclerosis.
