Novel potential pharmacological applications of dimethyl fumarate—an overview and update

Bresciani, Giorgia; Manai, Federico; Davinelli, Sergio; Tucci, Paolo; Saso, Luciano; Amadio, Marialaura

doi:10.3389/fphar.2023.1264842

Cited by 15 publications

(4 citation statements)

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“…Changes in the levels of the major cellular antioxidant glutathione (GSH) may lead to different forms of cell death, including apoptosis, ferroptosis and autophagy [ 45 , 46 ]. Given that DMF was previously reported to succinate GSH in other cellular models, we tested the ability of DMF to modulate the content of GSH in CLL cells.…”

Section: Resultsmentioning

confidence: 99%

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Mantione,

Meloni,

Sana

et al. 2024

Cell Death Dis

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Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.

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Section: Resultsmentioning

confidence: 99%

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Mantione,

Meloni,

Sana

et al. 2024

Cell Death Dis

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“…Notably, high inter-individual variability was also seen between both patients in the previous case series of Ciplea et al, with an AUC of 90 and 33 ng*h/mL, respectively. It is reported that the intake of DMF in combination with food, especially fatty food intake, can delay the peak concentration, but it is reported not to have a relevant effect on DMF subsequent exposure ( 2 , 3 ). Intake with food is also recommended to reduce flushing, which means that this combination reflects common practices, as in this case.…”

Section: Discussionmentioning

confidence: 99%

Very low monomethyl fumarate exposure via human milk: a case report—a contribution from the ConcePTION project

Van Neste,

Nauwelaerts,

Ceulemans

et al. 2024

Front. Public Health

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IntroductionWhile breastfeeding is recommended, knowledge regarding medicine transfer to human milk and its safety for nursing infants is limited. Only one paper has previously described dimethyl fumarate (DMF) transfer during breastfeeding in two patients at 5 and 6 months postpartum, respectively. The current case report describes maternal pharmacokinetic data of monomethyl fumarate (MMF), the active metabolite of DMF, and infant exposure estimations of MMF at 3 months postpartum.MethodsA 32-year-old Caucasian woman started DMF therapy (120 mg, 2x/day) for multiple sclerosis at 3 months postpartum, after weaning her infant from breastfeeding. On day 99 after birth, the patient collected four milk samples over 24 h after 6 days of treatment at the initial dose. Additionally, a single maternal blood sample was collected to calculate the milk-to-plasma (M/P) ratio. The samples were analyzed using liquid chromatography coupled with the mass spectrometry method.ResultsA wide range of measured steady-state concentrations of MMF (5.5-83.5 ng/mL) was observed in human milk samples. Estimated daily infant dosage values for MMF, calculated with 150 and 200 mL/kg/day human milk intake, were 5.76 and 7.68 μg/kg/day, and the relative infant doses were 0.16 and 0.22%. The observed mean M/P ratio was 0.059, similar to the M/P ratio predicted using the empirical Koshimichi model (0.06).DiscussionCombining this case report with the two previously described cases, the estimated infant exposure is low, albeit with relevant intra- and inter-patient variabilities. Research should further focus on infant exposure and safety.

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“…DMF also activates AKT pathways and thus promotes neuroprotection [ 178 ]. DMF upregulates several antioxidants including glutathione, bolstering the downstream antioxidant capacity in CNS conditions like MS, cerebral edema, TBI, and intracerebral hemorrhage [ 179 , 180 , 181 , 182 , 183 ]. DMF treatment in clinical settings has shown long-term efficacy in reducing relapse rates and minimizing lesion formation in relapsing forms of MS [ 184 ].…”

Section: Signaling Pathway Modulators For Cellular Antioxidant Synthesismentioning

confidence: 99%

Mitochondria-Targeted Antioxidant Therapeutics for Traumatic Brain Injury

Modi,

Musyaju,

Ratcliffe

et al. 2024

Antioxidants

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Traumatic brain injury (TBI) is a major global health problem that affects both civilian and military populations worldwide. Post-injury acute, sub-acute, and chronic progression of secondary injury processes may contribute further to other neurodegenerative diseases. However, there are no approved therapeutic options available that can attenuate TBI-related progressive pathophysiology. Recent advances in preclinical research have identified that mitochondria-centric redox imbalance, bioenergetics failure and calcium dysregulation play a crucial role in secondary injury progression after TBI. Mitochondrial antioxidants play an important role in regulating redox homeostasis. Based on the proven efficacy of preclinical and clinical compounds and targeting numerous pathways to trigger innate antioxidant defense, we may be able to alleviate TBI pathology progression by primarily focusing on preserving post-injury mitochondrial and cerebral function. In this review, we will discuss novel mitochondria-targeted antioxidant compounds, which offer a high capability of successful clinical translation for TBI management in the near future.

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Novel potential pharmacological applications of dimethyl fumarate—an overview and update

Cited by 15 publications

References 214 publications

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Very low monomethyl fumarate exposure via human milk: a case report—a contribution from the ConcePTION project

Mitochondria-Targeted Antioxidant Therapeutics for Traumatic Brain Injury

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